Deuterated analogs of MK2 inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplication No. 62/472,022, filed on Mar. 16, 2017, the entirety ofwhich is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of MK2kinases. The invention also provides pharmaceutically acceptablecompositions comprising compounds of the present invention and methodsof using said compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases are thought tohave evolved from a common ancestral gene due to the conservation oftheir structure and catalytic function. Almost all kinases contain asimilar 250-300 amino acid catalytic domain. The kinases may becategorized into families by the substrates they phosphorylate (e.g.,protein-tyrosine, protein-serine/threonine, lipids, etc.).

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2or MK2) mediates multiple p38 MAPK-dependent cellular responses. MK2 isan important intracellular regulator of the production of cytokines,such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) andinterferon gamma (IFNγ), that are involved in many acute and chronicinflammatory diseases, e.g. rheumatoid arthritis and inflammatory boweldisease. MK2 resides in the nucleus of non-stimulated cells and uponstimulation, it translocates to the cytoplasm and phosphorylates andactivates tuberin and HSP27. MK2 is also implicated in heart failure,brain ischemic injury, the regulation of stress resistance and theproduction of TNF-α. (see Deak et al., EMBO. 17:4426-4441 (1998); Shi etal., Biol. Chem. 383:1519-1536 (2002); Staklatvala., Curr. Opin.Pharmacol. 4:372-377 (2004), and Shiroto et al., J. Mol. Cardiol.38:93-97 (2005)).

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, autoimmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone-related diseases.Accordingly, there remains a need to find protein kinase inhibitorsuseful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of the present invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of MK2. Such compounds have general Formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) is as defined herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with abnormal cellular responsestriggered by protein kinase-mediated events. Such diseases, disorders,or conditions include those described herein.

Compounds provided by this invention are also useful for the study ofkinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of CertainAspects of the Invention

In certain embodiments, the present invention provides irreversibleinhibitors of MK2. In some embodiments, such compounds include those ofthe formulae described herein, or a pharmaceutically acceptable saltthereof, wherein each variable is as defined and described herein. Suchcompounds have the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each of R¹, R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷,        R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and        R^(yb) is independently selected from hydrogen or deuterium;    -   provided that at least one of R¹, R^(1′), R^(1″), R², R^(2′),        R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),        R^(xb), R^(ya), and R^(yb) is deuterium.

In some embodiments, the compound of Formula I is a compound other than

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of activity of a protein kinase, for example, MK2 or a mutantthereof, in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ transplantation,biological specimen storage, and biological assays.

As used herein, a “disease or disorder associated with MK2” or,alternatively, “an MK2-mediated disease or disorder” means any diseaseor other deleterious condition in which MK2, or a mutant thereof, isknown or suspected to play a role.

The term “subject”, as used herein, means a mammal and includes humanand animal subjects, such as domestic animals (e.g., horses, dogs, cats,etc.). The terms “subject” and “patient” are used interchangeably. Insome embodiments, the “patient” or “subject” means an animal, preferablya mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. The amount of compounds of the presentinvention that may be combined with the carrier materials to produce acomposition in a single dosage form will vary depending upon the hosttreated, the particular mode of administration, etc. Preferably,provided compositions are formulated so that a dosage of between 0.01 toabout 100 mg/kg, or about 0.1 mg/kg to about 50 mg/kg, and preferablyfrom about 1 mg/kg to about 25 mg/kg, of subject body weight/day of theinhibitor can be administered to a patient receiving these compositionsto obtain the desired therapeutic effect. The amount of a compound ofthe present invention in the composition will also depend upon theparticular compound in the composition.

The expression “unit dosage form” as used herein refers to a physicallydiscrete unit of a provided compound and/or compositions thereofappropriate for the subject to be treated. It will be understood,however, that the total daily usage of the active agent (i.e., compoundsand compositions of the present invention) will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular subject (i.e., patient)or organism will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; activity of specificactive agent employed; specific composition employed; age, body weight,general health, sex and diet of the subject; time of administration,route of administration, and rate of excretion of the specific activeagent employed; duration of the treatment; and like factors well knownin the medical arts.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques.

As used herein, a “therapeutically effective amount” means an amount ofa substance (e.g., a therapeutic agent, composition, and/or formulation)that elicits a desired biological response. In some embodiments, atherapeutically effective amount of a substance is an amount that issufficient, when administered as part of a dosing regimen to a subjectsuffering from or susceptible to a disease, disorder, and/or condition,to treat, diagnose, prevent, and/or delay the onset of the disease,disorder, and/or condition. As will be appreciated by those of ordinaryskill in this art, the effective amount of a substance may varydepending on such factors as the desired biological endpoint, thesubstance to be delivered, the target cell or tissue, etc. For example,the effective amount of a provided compound in a formulation to treat adisease, disorder, and/or condition is the amount that alleviates,ameliorates, relieves, inhibits, prevents, delays onset of, reducesseverity of and/or reduces incidence of one or more symptoms or featuresof the disease, disorder, and/or condition. In some embodiments, a“therapeutically effective amount” is at least a minimal amount of aprovided compound, or composition containing a provided compound, whichis sufficient for treating one or more symptoms of an MK2-mediateddisease or disorder.

As used herein, the terms “treatment,” “treat,” and “treating” refer topartially or completely alleviating, inhibiting, delaying onset of,preventing, ameliorating and/or relieving a disorder or condition, orone or more symptoms of the disorder or condition, as described herein.In some embodiments, treatment may be administered after one or moresymptoms have developed. In some embodiments, the term “treating”includes preventing or halting the progression of a disease or disorder.In other embodiments, treatment may be administered in the absence ofsymptoms. For example, treatment may be administered to a susceptibleindividual prior to the onset of symptoms (e.g., in light of a historyof symptoms and/or in light of genetic or other susceptibility factors).Treatment may also be continued after symptoms have resolved, forexample to prevent or delay their recurrence. Thus, in some embodiments,the term “treating” includes preventing relapse or recurrence of adisease or disorder.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits the target protein kinase, MK2, with measurableaffinity. In certain embodiments, an inhibitor has an IC₅₀ and/orbinding constant of less than about 50 μM, less than about 1 μM, lessthan about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in MK2 activity between a samplecomprising a compound of the present invention, or composition thereof,and MK2, and an equivalent sample comprising MK2, in the absence of saidcompound, or composition thereof.

As used herein, the term “irreversible” or “irreversible inhibitor”refers to an inhibitor (i.e. a compound) that is able to be covalentlybonded to a kinase in a substantially non-reversible manner. That is,whereas a reversible inhibitor is able to bind to (but is generallyunable to form a covalent bond with) a kinase, and therefore can becomedissociated from the kinase, an irreversible inhibitor will remainsubstantially bound to a kinase once covalent bond formation hasoccurred. Irreversible inhibitors usually display time dependency,whereby the degree of inhibition increases with the time with which theinhibitor is in contact with the enzyme. In certain embodiments, anirreversible inhibitor will remain substantially bound to a kinase oncecovalent bond formation has occurred and will remain bound for a timeperiod that is longer than the life of the protein.

Methods for identifying if a compound is an irreversible inhibitor areknown to one of ordinary skill in the art. Such methods include, but arenot limited to, enzyme kinetic analysis of the inhibition profile of thecompound with a kinase, the use of mass spectrometry of the protein drugtarget modified in the presence of the inhibitor compound, discontinuousexposure, also known as “washout,” experiments, and the use of labeling,such as radiolabelled inhibitor, to show covalent modification of theenzyme, as well as other methods known to one of skill in the art.

As used herein, the term “drug resistance” refers to changes in thewild-type nucleic acid sequence coding a target protein, and/or theamino acid sequence of the target protein, and/or the amino acidsequence of another protein, which changes or decreases or abolishes theinhibitory effect of the inhibitor on the target protein. Withoutwishing to be bound by any particular theory, it is believed thatcertain compounds of the present invention, i.e., compounds that areirreversible kinase inhibitors, may be effective inhibitors of drugresistant forms of protein kinases.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each of R¹, R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷,        R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and        R^(yb) is independently selected from hydrogen or deuterium;    -   provided that at least one of R¹, R^(1′), R^(1″), R², R^(2′),        R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),        R^(xb), R^(ya), and R^(yb) is deuterium.

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas an atomic weight of 2.0144. Hydrogen naturally occurs as a mixtureof the isotopes ¹H (hydrogen or protium), D (2H or deuterium), and T (³Hor tritium). It will be appreciated that the designation “hydrogen” inhydrogen-containing chemical compounds actually represents a mixture ofhydrogen and about 0.015% deuterium.

Complete deuteration, or 100% deuteration, at any one site can bedifficult to achieve in the laboratory. When a deuterium atom isindicated at a given site on any compound described herein, it isunderstood that a small percentage of hydrogen may still be present.Such compounds are said to be enriched with deuterium.Deuterium-enriched compounds are prepared via synthesis utilizingappropriately enriched starting materials. As used herein, the terms“deuterium-enriched” or “deuterium enrichment” refer to a compound, or aparticular site of said compound, which comprises deuterium in an amountthat is greater than its natural isotopic abundance (0.015%).Accordingly, in some embodiments, the present invention providescompounds comprising deuterium at a given site, wherein the percentageor level of deuterium incorporation is greater than its natural isotopicabundance.

In some embodiments, the present invention provides a compound ofFormulae I′ or I″:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8″), R⁹,R^(xa), R^(xb), R^(ya), and R^(yb) is as defined herein.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R^(1′) is hydrogen. In some embodiments,R^(1′) is deuterium. In some embodiments, R^(1″) is hydrogen. In someembodiments, R^(1″) is deuterium.

In some embodiments, R¹, R^(1′), and R^(1″) are different. In someembodiments, each of R¹ and R^(1′) is hydrogen and R^(1″) is deuterium.In some embodiments, each of R¹ and R^(1″) is hydrogen and R^(1′) isdeuterium. In some embodiments, each of R^(1′) and R^(1″) is hydrogenand R¹ is deuterium. In some embodiments, R¹ is hydrogen and each of R¹and R^(1″) is deuterium. In some embodiments, R^(1′) is hydrogen andeach of R¹ and R^(1″) is deuterium. In some embodiments, R^(1″) ishydrogen and each of R¹ and R^(1′) is deuterium.

In some embodiments, R¹, R^(1′), and R^(1″) are the same. In someembodiments, each of R¹, R^(1′), and R^(1″) is deuterium. In someembodiments, each of R¹, R^(1′), and R^(1″) is deuterium and each of R²,R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8″), R⁹, R^(xa), R^(xb),R^(ya), and R^(yb) is hydrogen. In some embodiments, each of R¹, R^(1′),and R^(1″) is deuterium and at least one of R², R^(2′), R³, R^(3′), R⁴,R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb)is deuterium. In some embodiments, each of R¹, R^(1′), and R^(1″) ishydrogen.

In some embodiments, R² is hydrogen. In some embodiments, R² isdeuterium. In some embodiments, R^(2′) is hydrogen. In some embodiments,R^(2′) is deuterium.

In some embodiments, R² and R^(2′) are different. In some embodiments,R² is hydrogen and R^(2′) is deuterium. In some embodiments, R² isdeuterium and R^(2′) is hydrogen.

In some embodiments, R² and R^(2′) are the same. In some embodiments,each of R² and R^(2′) is deuterium. In some embodiments, each of R² andR^(2′) is deuterium and each of R¹, R^(1′), R^(1″), R³, R^(3′), R⁴, R⁷,R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) ishydrogen. In some embodiments, each of R² and R^(2′) is deuterium and atleast one of R¹, R^(1′), R^(1″), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) is deuterium. In someembodiments, each of R² and R^(2′) is hydrogen.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R^(3′) is hydrogen. In some embodiments,R^(3′) is deuterium.

In some embodiments, R³ and R^(3′) are different. In some embodiments,R³ is hydrogen and R^(3′) is deuterium. In some embodiments, R³ isdeuterium and R^(3′) is hydrogen.

In some embodiments, R³ and R^(3′) are the same. In some embodiments,each of R³ and R^(3′) is deuterium. In some embodiments, each of R³ andR^(3′) is deuterium and each of R¹, R^(1′), R^(1″), R², R^(2′), R⁴, R⁷,R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) ishydrogen. In some embodiments, each of R³ and R^(3′) is deuterium and atleast one of R¹, R^(1′), R^(1″), R², R^(2′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) is deuterium. In someembodiments, each of R³ and R^(3′) is hydrogen.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ isdeuterium. In some embodiments, R⁴ is deuterium and each of R¹, R^(1′),R^(1″), R², R^(2′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),R^(xb), R^(ya), and R^(yb) is hydrogen. In some embodiments, R⁴ isdeuterium and at least one of R¹, R^(1′), R^(1″), R², R^(2′), R⁴, R⁷,R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) isdeuterium.

In some embodiments, R⁷ is hydrogen. In some embodiments, R⁷ isdeuterium. In some embodiments, R^(7′) is hydrogen. In some embodiments,R^(7′) is deuterium.

In some embodiments, R⁷ and R^(7′) are different. In some embodiments,R⁷ is hydrogen and R^(7′) is deuterium. In some embodiments, R⁷ isdeuterium and R^(7′) is hydrogen.

In some embodiments, R⁷ and R^(7′) are the same. In some embodiments,each of R⁷ and R^(7′) is deuterium. In some embodiments, each of R⁷ andR^(7′) is deuterium and each of R¹, R^(1′), R^(1″), R², R^(2′), R³,R^(3′), R⁴, R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb)is hydrogen. In some embodiments, each of R⁷ and R^(7′) is deuterium andat least one of R¹, R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁸,R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) is deuterium. Insome embodiments, each of R⁷ and R^(7′) is hydrogen.

In some embodiments, R⁸ is hydrogen. In some embodiments, R⁸ isdeuterium. In some embodiments, R^(8′) is hydrogen. In some embodiments,R^(8′) is deuterium. In some embodiments, R^(8″) is hydrogen. In someembodiments, R^(8″) is deuterium.

In some embodiments, R⁸, R^(8′), and R^(8″) are different. In someembodiments, each of R⁸ and R^(8′) is hydrogen and R^(8″) is deuterium.In some embodiments, each of R⁸ and R^(8″) is hydrogen and R^(8′) isdeuterium. In some embodiments, each of R^(8′) and R^(8″) is hydrogenand R⁸ is deuterium. In some embodiments, R⁸ is hydrogen and each ofR^(8′) and R^(8″) is deuterium. In some embodiments, R^(8′) is hydrogenand each of R⁸ and R^(8″) is deuterium. In some embodiments, R^(8″) ishydrogen and each of R⁸ and R^(8′) is deuterium.

In some embodiments, R⁸, R^(8′), and R^(8″) are the same. In someembodiments, each of R⁸, R^(8′), and R^(8″) is deuterium. In someembodiments, each of R⁸, R^(8′), and R^(8″) is deuterium and each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁹, R^(xa),R^(xb), R^(ya), and R^(yb) is hydrogen. In some embodiments, each of R⁸,R^(8′), and R^(8″) is deuterium and at least one of R¹, R^(1′), R^(1″),R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁹, R^(xa), R^(xb), R^(ya), andR^(yb) is deuterium. In some embodiments, each of R⁸, R^(8′), and R^(8″)is hydrogen.

In some embodiments, R⁹ is hydrogen. In some embodiments, R⁹ isdeuterium. In some embodiments, R⁹ is deuterium and each of R¹, R^(1′),R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″),R^(xa), R^(xb), R^(ya), and R^(yb) is hydrogen. In some embodiments, R⁹is deuterium and at least one of R¹, R^(1′), R^(1″), R², R^(2′), R³,R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R^(xa), R^(xb), R^(ya), andR^(yb) is deuterium.

In some embodiments, R^(xa) is hydrogen. In some embodiments, R^(xa) isdeuterium. In some embodiments, R^(xb) is hydrogen. In some embodiments,R^(xb) is deuterium.

In some embodiments, R^(xa) and R^(xb) are different. In someembodiments, R^(xa) is hydrogen and R^(xb) is deuterium. In someembodiments, R^(xa) is deuterium and R^(xb) is hydrogen.

In some embodiments, R^(xa) and R^(xb) are the same. In someembodiments, each of R^(xa) and R^(xb) is deuterium. In someembodiments, each of R^(xa) and R^(xb) is deuterium and each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), R⁹, R^(ya), and R^(yb) is hydrogen. In some embodiments, each ofR^(xa) and R^(xb) is deuterium and at least one of R¹, R^(1′), R^(1″),R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(ya),and R^(yb) is deuterium. In some embodiments, each of R^(xa) and R^(xb)is hydrogen.

In some embodiments, R^(ya) is hydrogen. In some embodiments, R^(ya) isdeuterium. In some embodiments, R^(yb) is hydrogen. In some embodiments,R^(yb) is deuterium.

In some embodiments, R^(ya) and R^(yb) are different. In someembodiments, R^(ya) is hydrogen and R^(yb) is deuterium. In someembodiments, R^(ya) is deuterium and R^(yb) is hydrogen.

In some embodiments, R^(ya) and R^(yb) are the same. In someembodiments, each of R^(ya) and R^(yb) is deuterium. In someembodiments, each of R^(ya) and R^(yb) is deuterium and each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), R⁹, R^(xa), and R^(xb) is hydrogen. In some embodiments, each ofR^(ya) and R^(yb) is deuterium and at least one of R¹, R^(1′), R^(1″),R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),and R^(xb) is deuterium. In some embodiments, each of R^(ya) and R^(yb)is hydrogen.

In some embodiments, each of R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) is deuterium. In someembodiments, each of R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹,R^(xa), R^(xb), R^(ya), and R^(yb) is hydrogen. Accordingly, in someembodiments, the present invention provides a compound of Formulae II,II′ or II″:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², and R^(2′) is as defined above and described herein,provided that at least one of R¹, R^(1′), R^(1″), R², and R^(2′) isdeuterium.

In some embodiments, a compound of Formulae II, II′ or II″ is selectedfrom the compounds in Table 1.

TABLE 1 Compounds of Formulae II, II′ or II″. Formula Formula Formula IIII′ II″ R¹ R^(1′) R^(1″) R² R^(2′) II-1 II′-1 II″-1 D H H H H II-2 II′-2II″-2 H D H H H II-3 II′-3 II″-3 H H D H H II-4 II′-4 II″-4 D D H H HII-5 II′-5 II″-5 D H D H H II-6 II′-6 II″-6 H D D H H II-7 II′-7 II″-7 DD D H H II-8 II′-8 II″-8 H H H H D II-9 II′-9 II″-9 D H H H D II-10II′-10 II″-10 H D H H D II-11 II′-11 II″-11 H H D H D II-12 II′-12II″-12 D D H H D II-13 II′-13 II″-13 D H D H D II-14 II′-14 II″-14 H D DH D II-15 II′-15 II″-15 D D D H D II-16 II′-16 II″-16 H H H D H II-17II′-17 II″-17 D H H D H II-18 II′-18 II″-18 H D H D H II-19 II′-19II″-19 H H D D H II-20 II′-20 II″-20 D D H D H II-21 II′-21 II″-21 D H DD H II-22 II′-22 II″-22 H D D D H II-23 II′-23 II″-23 D D D D H II-24II′-24 II″-24 H H H D D II-25 II′-25 II″-25 D H H D D II-26 II′-26II″-26 H D H D D II-27 II′-27 II″-27 H H D D D II-28 II′-28 II″-28 D D HD D II-29 II′-29 II″-29 D H D D D II-30 II′-30 II″-30 H D D D D II-31II′-31 II″-31 D D D D D

In some embodiments, each of R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),R^(xb), R^(ya), and R^(yb) is deuterium. In some embodiments, each ofR⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb)is hydrogen. Accordingly, in some embodiments, the present inventionprovides a compound of Formulae III, III′ or III″:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), and R⁴ is as defined above anddescribed herein, provided that at least one of R¹, R^(1′), R^(1″), R²,R^(2′), R³, R^(3′), and R⁴ is deuterium.

In some embodiments, a compound of Formulae III, III′ or III″ isselected from the compounds in Table 2.

TABLE 2 Compounds of Formulae III, III′ or III″. Formula Formula FormulaIII III′ III″ R¹/R^(1′)/R^(1″) R²/R^(2′) R³/R^(3′) R⁴ III-1 III′-1III″-1 D H H H III-2 III′-2 III″-2 H D H H III-3 III′-3 III″-3 H H D HIII-4 III′-4 III″-4 D D H H III-5 III′-5 III″-5 D H D H III-6 III′-6III″-6 H D D H III-7 III′-7 III″-7 D D D H III-8 III′-8 III″-8 H H H DIII-9 III′-9 III″-9 D H H D III-10 III′-10 III″-10 H D H D III-11III′-11 III″-11 H H D D III-12 III′-12 III″-12 D D H D III-13 III′-13III″-13 D H D D III-14 III′-14 III″-14 H D D D III-15 III′-15 III″-15 DD D D

In some embodiments, each of each of R¹, R^(1′), R^(1″), R², R^(2′), R³,R^(3′), R⁴, R^(xa), R^(xb), R^(ya), and R^(yb) is deuterium. In someembodiments, each of each of R¹, R^(1′), R^(1″), R², R^(2′), R³, R^(3′),R⁴, R^(xa), R^(xb), R^(ya), and R^(yb) is hydrogen. Accordingly, in someembodiments, the present invention provides a compound of Formulae IV,IV′ or IV″:

or a pharmaceutically acceptable salt thereof, wherein each of R⁷,R^(7′), R⁸, R^(8′), R^(8″), and R⁹ is as defined above and describedherein, provided that at least one of R⁷, R^(7′), R⁸, R^(8′), R^(8″),and R⁹ is deuterium.

In some embodiments, a compound of Formulae IV, IV′ or IV″ is selectedfrom those in Table 3.

TABLE 3 Compounds of Formulae IV, IV′ or IV″. Formula Formula Formula IVIV′ IV″ R⁷ R^(7′) R⁸ R^(8′) R^(8″) R⁹ IV-1 IV′-1 IV″-1 H H D H H H IV-2IV′-2 IV″-2 H H H D H H IV-3 IV′-3 IV″-3 H H H H D H IV-4 IV′-4 IV″-4 HH D D H H IV-5 IV′-5 IV″-5 H H D H D H IV-6 IV′-6 IV″-6 H H H D D H IV-7IV′-7 IV″-7 H H D D D H IV-8 IV′-8 IV″-8 H D H H H H IV-9 IV′-9 IV″-9 HD D H H H IV-10 IV′-10 IV″-10 H D H D H H IV-11 IV′-11 IV″-11 H D H H DH IV-12 IV′-12 IV″-12 H D D D H H IV-13 IV′-13 IV″-13 H D D H D H IV-14IV′-14 IV″-14 H D H D D H IV-15 IV′-15 IV″-15 H D D D D H IV-16 IV′-16IV″-16 D H H H H H IV-17 IV′-17 IV″-17 D H D H H H IV-18 IV′-18 IV″-18 DH H D H H IV-19 IV′-19 IV″-19 D H H H D H IV-20 IV′-20 IV″-20 D H D D HH IV-21 IV′-21 IV″-21 D H D H D H IV-22 IV′-22 IV″-22 D H H D D H IV-23IV′-23 IV″-23 D H D D D H IV-24 IV′-24 IV″-24 D D H H H H IV-25 IV′-25IV″-25 D D D H H H IV-26 IV′-26 IV″-26 D D H D H H IV-27 IV′-27 IV″-27 DD H H D H IV-28 IV′-28 IV″-28 D D D D H H IV-29 IV′-29 IV″-29 D D D H DH IV-30 IV′-30 IV″-30 D D H D D H IV-31 IV′-31 IV″-31 D D D D D H IV-32IV′-32 IV″-32 H H H H H D IV-33 IV′-33 IV″-33 H H D H H D IV-34 IV′-34IV″-34 H H H D H D IV-35 IV′-35 IV″-35 H H H H D D IV-36 IV′-36 IV″-36 HH D D H D IV-37 IV′-37 IV″-37 H H D H D D IV-38 IV′-38 IV″-38 H H H D DD IV-39 IV′-39 IV″-39 H H D D D D IV-40 IV′-40 IV″-40 H D H H H D IV-41IV′-41 IV″-41 H D D H H D IV-42 IV′-42 IV″-42 H D H D H D IV-43 IV′-43IV″-43 H D H H D D IV-44 IV′-44 IV″-44 H D D D H D IV-45 IV′-45 IV″-45 HD D H D D IV-46 IV′-46 IV″-46 H D H D D D IV-47 IV′-47 IV″-47 H D D D DD IV-48 IV′-48 IV″-48 D H H H H D IV-49 IV′-49 IV″-49 D H D H H D IV-50IV′-50 IV″-50 D H H D H D IV-51 IV′-51 IV″-51 D H H H D D IV-52 IV′-52IV″-52 D H D D H D IV-53 IV′-53 IV″-53 D H D H D D IV-54 IV′-54 IV″-54 DH H D D D IV-55 IV′-55 IV″-55 D H D D D D IV-56 IV′-56 IV″-56 D D H H HD IV-57 IV′-57 IV″-57 D D D H H D IV-58 IV′-58 IV″-58 D D H D H D IV-59IV′-59 IV″-59 D D H H D D IV-60 IV′-60 IV″-60 D D D D H D IV-61 IV′-61IV″-61 D D D H D D IV-62 IV′-62 IV″-62 D D H D D D IV-63 IV′-63 IV″-63 DD D D D D

In some embodiments, each of R³, R^(3′), R⁴, R^(xa), R^(xb), R^(ya), andR^(yb) is deuterium. In some embodiments, each of R³, R^(3′), R⁴,R^(xa), R^(xb), R^(ya), and R^(yb) is hydrogen. Accordingly, in someembodiments, the present invention provides a compound of Formulae V, V′or V″:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², R^(2′), R⁷, R^(7′), R⁸, R^(8′), R^(8″), and R⁹ is asdefined above and described herein, provided that at least one of R¹,R^(1′), R^(1″), R², R^(2′), R⁷, R^(7′), R⁸, R^(8′), R^(8″), and R⁹ isdeuterium.

In some embodiments, a compound of Formulae V, V′ or V″ is selected fromthose in Table 4:

TABLE 4 Compounds of Formulae V, V′ or V″. Formula Formula FormulaR¹/R^(1′)/ R⁸/R^(8′)/ V V′ V″ R^(1″) R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹ V-1V′-1 V″-1 D H D H H V-2 V′-2 V″-2 D H H D H V-3 V′-3 V″-3 D H H H D V-4V′-4 V″-4 D H D D H V-5 V′-5 V″-5 D H D H D V-6 V′-6 V″-6 D H H D D V-7V′-7 V″-7 D H D D D V-8 V′-8 V″-8 H D D H H V-9 V′-9 V″-9 H D H D H V-10V′-10 V″-10 H D H H D V-11 V′-11 V″-11 H D D D H V-12 V′-12 V″-12 H D DH D V-13 V′-13 V″-13 H D H D D V-14 V′-14 V″-14 H D D D D V-15 V′-15V″-15 D D D H H V-16 V′-16 V″-16 D D H D H V-17 V′-17 V″-17 D D H H DV-18 V′-18 V″-18 D D D D H V-19 V′-19 V″-19 D D D H D V-20 V′-20 V″-20 DD H D D V-21 V′-21 V″-21 D D D D D

In some embodiments, each of R³, R^(3′), and R⁴ is deuterium. In someembodiments, each of R³, R^(3′), and R⁴ is hydrogen. Accordingly, insome embodiments, the present invention provides a compound of FormulaeVI, VI′ or VI″:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², R^(2′), R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),R^(xb), R^(ya), and R^(yb) is as defined above and described herein,provided that at least one of R¹, R^(1′), R^(1″), R², R^(2′), R⁷,R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and R^(yb) isdeuterium.

In some embodiments of Formulae VI, VI′ or VI″, at least one of R¹,R^(1′), R^(1″), R², R^(2′), R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),R^(xb), R^(ya), and R^(yb) is deuterium. In some embodiments of FormulaeVI, VI′ or VI″, the compound is selected from those in Table 5, Table 6,Table 7 and Table 8:

TABLE 5 Compounds of Formulae VI, VI′ or VI″, wherein each of R^(ya) andR^(yb) is hydrogen. Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/R⁸/R^(8′)/ VI VI′ VI″ R^(1″) R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb) VI-1VI′-1 VI″-1 H H H H H H D VI-2 VI′-2 VI″-2 H H D H H H D VI-3 VI′-3VI″-3 H H H D H H D VI-4 VI′-4 VI″-4 H H H H D H D VI-5 VI′-5 VI″-5 H HD D H H D VI-6 VI′-6 VI″-6 H H D H D H D VI-7 VI′-7 VI″-7 H H H D D H DVI-8 VI′-8 VI″-8 H H D D D H D VI-9 VI′-9 VI″-9 H D H H H H D VI-10VI′-10 VI″-10 H D D H H H D VI-11 VI′-11 VI″-11 H D H D H H D VI-12VI′-12 VI″-12 H D H H D H D VI-13 VI′-13 VI″-13 H D D D H H D VI-14VI′-14 VI″-14 H D D H D H D VI-15 VI′-15 VI″-15 H D H D D H D VI-16VI′-16 VI″-16 H D D D D H D VI-17 VI′-17 VI″-17 D H H H H H D VI-18VI′-18 VI″-18 D H D H H H D VI-19 VI′-19 VI″-19 D H H D H H D VI-20VI′-20 VI″-20 D H H H D H D VI-21 VI′-21 VI″-21 D H D D H H D VI-22VI′-22 VI″-22 D H D H D H D VI-23 VI′-23 VI″-23 D H H D D H D VI-24VI′-24 VI″-24 D H D D D H D VI-25 VI′-25 VI″-25 D D H H H H D VI-26VI′-26 VI″-26 D D D H H H D VI-27 VI′-27 VI″-27 D D H D H H D VI-28VI′-28 VI″-28 D D H H D H D VI-29 VI′-29 VI″-29 D D D D H H D VI-30VI′-30 VI″-30 D D D H D H D VI-31 VI′-31 VI″-31 D D H D D H D VI-32VI′-32 VI″-32 D D D D D H D VI-33 VI′-33 VI″-33 H H H H H D H VI-34VI′-34 VI″-34 H H D H H D H VI-35 VI′-35 VI″-35 H H H D H D H VI-36VI′-36 VI″-36 H H H H D D H VI-37 VI′-37 VI″-37 H H D D H D H VI-38VI′-38 VI″-38 H H D H D D H VI-39 VI′-39 VI″-39 H H H D D D H VI-40VI′-40 VI″-40 H H D D D D H VI-41 VI′-41 VI″-41 H D H H H D H VI-42VI′-42 VI″-42 H D D H H D H VI-43 VI′-43 VI″-43 H D H D H D H VI-44VI′-44 VI″-44 H D H H D D H VI-45 VI′-45 VI″-45 H D D D H D H VI-46VI′-46 VI″-46 H D D H D D H VI-47 VI′-47 VI″-47 H D H D D D H VI-48VI′-48 VI″-48 H D D D D D H VI-49 VI′-49 VI″-49 D H H H H D H VI-50VI′-50 VI″-50 D H D H H D H VI-51 VI′-51 VI″-51 D H H D H D H VI-52VI′-52 VI″-52 D H H H D D H VI-53 VI′-53 VI″-53 D H D D H D H VI-54VI′-54 VI″-54 D H D H D D H VI-55 VI′-55 VI″-55 D H H D D D H VI-56VI′-56 VI″-56 D H D D D D H VI-57 VI′-57 VI″-57 D D H H H D H VI-58VI′-58 VI″-58 D D D H H D H VI-59 VI′-59 VI″-59 D D H D H D H VI-60VI′-60 VI″-60 D D H H D D H VI-61 VI′-61 VI″-61 D D D D H D H VI-62VI′-62 VI″-62 D D D H D D H VI-63 VI′-63 VI″-63 D D H D D D H VI-64VI′-64 VI″-64 D D D D D D H VI-65 VI′-65 VI″-65 H H H H H D D VI-66VI′-66 VI″-66 H H D H H D D VI-67 VI′-67 VI″-67 H H H D H D D VI-68VI′-68 VI″-68 H H H H D D D VI-69 VI′-69 VI″-69 H H D D H D D VI-70VI′-70 VI″-70 H H D H D D D VI-71 VI′-71 VI″-71 H H H D D D D VI-72VI′-72 VI″-72 H H D D D D D VI-73 VI′-73 VI″-73 H D H H H D D VI-74VI′-74 VI″-74 H D D H H D D VI-75 VI′-75 VI″-75 H D H D H D D VI-76VI′-76 VI″-76 H D H H D D D VI-77 VI′-77 VI″-77 H D D D H D D VI-78VI′-78 VI″-78 H D D H D D D VI-79 VI′-79 VI″-79 H D H D D D D VI-80VI′-80 VI″-80 H D D D D D D VI-81 VI′-81 VI″-81 D H H H H D D VI-82VI′-82 VI″-82 D H D H H D D VI-83 VI′-83 VI″-83 D H H D H D D VI-84VI′-84 VI″-84 D H H H D D D VI-85 VI′-85 VI″-85 D H D D H D D VI-86VI′-86 VI″-86 D H D H D D D VI-87 VI′-87 VI″-87 D H H D D D D VI-88VI′-88 VI″-88 D H D D D D D VI-89 VI′-89 VI″-89 D D H H H D D VI-90VI′-90 VI″-90 D D D H H D D VI-91 VI′-91 VI″-91 D D H D H D D VI-92VI′-92 VI″-92 D D H H D D D VI-93 VI′-93 VI″-93 D D D D H D D VI-94VI′-94 VI″-94 D D D H D D D VI-95 VI′-95 VI″-95 D D H D D D D VI-96VI′-96 VI″-96 D D D D D D D

TABLE 6 Compounds of Formulae VI, VI′ or VI″, wherein each of R^(ya) andR^(yb) is deuterium. Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/R⁸/R^(8′)/ VI VI′ VI″ R^(1″) R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb) VI-97VI′-97 VI″-97 H H H H H H H VI-98 VI′-98 VI″-98 H H D H H H H VI-99VI′-99 VI″-99 H H H D H H H VI-100 VI′-100 VI″-100 H H H H D H H VI-101VI′-101 VI″-101 H H D D H H H VI-102 VI′-102 VI″-102 H H D H D H HVI-103 VI′-103 VI″-103 H H H D D H H VI-104 VI′-104 VI″-104 H H D D D HH VI-105 VI′-105 VI″-105 H D H H H H H VI-106 VI′-106 VI″-106 H D D H HH H VI-107 VI′-107 VI″-107 H D H D H H H VI-108 VI′-108 VI″-108 H D H HD H H VI-109 VI′-109 VI″-109 H D D D H H H VI-110 VI′-110 VI″-110 H D DH D H H VI-111 VI′-111 VI″-111 H D H D D H H VI-112 VI′-112 VI″-112 H DD D D H H VI-113 VI′-113 VI″-113 D H H H H H H VI-114 VI′-114 VI″-114 DH D H H H H VI-115 VI′-115 VI″-115 D H H D H H H VI-116 VI′-116 VI″-116D H H H D H H VI-117 VI′-117 VI″-117 D H D D H H H VI-118 VI′-118VI″-118 D H D H D H H VI-119 VI′-119 VI″-119 D H H D D H H VI-120VI′-120 VI″-120 D H D D D H H VI-121 VI′-121 VI″-121 D D H H H H HVI-122 VI′-122 VI″-122 D D D H H H H VI-123 VI′-123 VI″-123 D D H D H HH VI-124 VI′-124 VI″-124 D D H H D H H VI-125 VI′-125 VI″-125 D D D D HH H VI-126 VI′-126 VI″-126 D D D H D H H VI-127 VI′-127 VI″-127 D D H DD H H VI-128 VI′-128 VI″-128 D D D D D H H VI-129 VI′-129 VI″-129 H H HH H H D VI-130 VI′-130 VI″-130 H H D H H H D VI-131 VI′-131 VI″-131 H HH D H H D VI-132 VI′-132 VI″-132 H H H H D H D VI-133 VI′-133 VI″-133 HH D D H H D VI-134 VI′-134 VI″-134 H H D H D H D VI-135 VI′-135 VI″-135H H H D D H D VI-136 VI′-136 VI″-136 H H D D D H D VI-137 VI′-137VI″-137 H D H H H H D VI-138 VI′-138 VI″-138 H D D H H H D VI-139VI′-139 VI″-139 H D H D H H D VI-140 VI′-140 VI″-140 H D H H D H DVI-141 VI′-141 VI″-141 H D D D H H D VI-142 VI′-142 VI″-142 H D D H D HD VI-143 VI′-143 VI″-143 H D H D D H D VI-144 VI′-144 VI″-144 H D D D DH D VI-145 VI′-145 VI″-145 D H H H H H D VI-146 VI′-146 VI″-146 D H D HH H D VI-147 VI′-147 VI″-147 D H H D H H D VI-148 VI′-148 VI″-148 D H HH D H D VI-149 VI′-149 VI″-149 D H D D H H D VI-150 VI′-150 VI″-150 D HD H D H D VI-151 VI′-151 VI″-151 D H H D D H D VI-152 VI′-152 VI″-152 DH D D D H D VI-153 VI′-153 VI″-153 D D H H H H D VI-154 VI′-154 VI″-154D D D H H H D VI-155 VI′-155 VI″-155 D D H D H H D VI-156 VI′-156VI″-156 D D H H D H D VI-157 VI′-157 VI″-157 D D D D H H D VI-158VI′-158 VI″-158 D D D H D H D VI-159 VI′-159 VI″-159 D D H D D H DVI-160 VI′-160 VI″-160 D D D D D H D VI-161 VI′-161 VI″-161 H H H H H DH VI-162 VI′-162 VI″-162 H H D H H D H VI-163 VI′-163 VI″-163 H H H D HD H VI-164 VI′-164 VI″-164 H H H H D D H VI-165 VI′-165 VI″-165 H H D DH D H VI-166 VI′-166 VI″-166 H H D H D D H VI-167 VI′-167 VI″-167 H H HD D D H VI-168 VI′-168 VI″-168 H H D D D D H VI-169 VI′-169 VI″-169 H DH H H D H VI-170 VI′-170 VI″-170 H D D H H D H VI-171 VI′-171 VI″-171 HD H D H D H VI-172 VI′-172 VI″-172 H D H H D D H VI-173 VI′-173 VI″-173H D D D H D H VI-174 VI′-174 VI″-174 H D D H D D H VI-175 VI′-175VI″-175 H D H D D D H VI-176 VI′-176 VI″-176 H D D D D D H VI-177VI′-177 VI″-177 D H H H H D H VI-178 VI′-178 VI″-178 D H D H H D HVI-179 VI′-179 VI″-179 D H H D H D H VI-180 VI′-180 VI″-180 D H H H D DH VI-181 VI′-181 VI″-181 D H D D H D H VI-182 VI′-182 VI″-182 D H D H DD H VI-183 VI′-183 VI″-183 D H H D D D H VI-184 VI′-184 VI″-184 D H D DD D H VI-185 VI′-185 VI″-185 D D H H H D H VI-186 VI′-186 VI″-186 D D DH H D H VI-187 VI′-187 VI″-187 D D H D H D H VI-188 VI′-188 VI″-188 D DH H D D H VI-189 VI′-189 VI″-189 D D D D H D H VI-190 VI′-190 VI″-190 DD D H D D H VI-191 VI′-191 VI″-191 D D H D D D H VI-192 VI′-192 VI″-192D D D D D D H VI-193 VI′-193 VI″-193 H H H H H D D VI-194 VI′-194VI″-194 H H D H H D D VI-195 VI′-195 VI″-195 H H H D H D D VI-196VI′-196 VI″-196 H H H H D D D VI-197 VI′-197 VI″-197 H H D D H D DVI-198 VI′-198 VI″-198 H H D H D D D VI-199 VI′-199 VI″-199 H H H D D DD VI-200 VI′-200 VI″-200 H H D D D D D VI-201 VI′-201 VI″-201 H D H H HD D VI-202 VI′-202 VI″-202 H D D H H D D VI-203 VI′-203 VI″-203 H D H DH D D VI-204 VI′-204 VI″-204 H D H H D D D VI-205 VI′-205 VI″-205 H D DD H D D VI-206 VI′-206 VI″-206 H D D H D D D VI-207 VI′-207 VI″-207 H DH D D D D VI-208 VI′-208 VI″-208 H D D D D D D VI-209 VI′-209 VI″-209 DH H H H D D VI-210 VI′-210 VI″-210 D H D H H D D VI-211 VI′-211 VI″-211D H H D H D D VI-212 VI′-212 VI″-212 D H H H D D D VI-213 VI′-213VI″-213 D H D D H D D VI-214 VI′-214 VI″-214 D H D H D D D VI-215VI′-215 VI″-215 D H H D D D D VI-216 VI′-216 VI″-216 D H D D D D DVI-217 VI′-217 VI″-217 D D H H H D D VI-218 VI′-218 VI″-218 D D D H H DD VI-219 VI′-219 VI″-219 D D H D H D D VI-220 VI′-220 VI″-220 D D H H DD D VI-221 VI′-221 VI″-221 D D D D H D D VI-222 VI′-222 VI″-222 D D D HD D D VI-223 VI′-223 VI″-223 D D H D D D D VI-224 VI′-224 VI″-224 D D DD D D D

TABLE 7 Compounds of Formulae VI, VI′ or VI″, wherein R^(ya) is hydrogenand R^(yb) is deuterium. Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/R⁸/R^(8′)/ VI VI′ VI″ R^(1″) R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb)VI-225 VI′-225 VI″-225 H H H H H H H VI-226 VI′-226 VI″-226 H H D H H HH VI-227 VI′-227 VI″-227 H H H D H H H VI-228 VI′-228 VI″-228 H H H H DH H VI-229 VI′-229 VI″-229 H H D D H H H VI-230 VI′-230 VI″-230 H H D HD H H VI-231 VI′-231 VI″-231 H H H D D H H VI-232 VI′-232 VI″-232 H H DD D H H VI-233 VI′-233 VI″-233 H D H H H H H VI-234 VI′-234 VI″-234 H DD H H H H VI-235 VI′-235 VI″-235 H D H D H H H VI-236 VI′-236 VI″-236 HD H H D H H VI-237 VI′-237 VI″-237 H D D D H H H VI-238 VI′-238 VI″-238H D D H D H H VI-239 VI′-239 VI″-239 H D H D D H H VI-240 VI′-240VI″-240 H D D D D H H VI-241 VI′-241 VI″-241 D H H H H H H VI-242VI′-242 VI″-242 D H D H H H H VI-243 VI′-243 VI″-243 D H H D H H HVI-244 VI′-244 VI″-244 D H H H D H H VI-245 VI′-245 VI″-245 D H D D H HH VI-246 VI′-246 VI″-246 D H D H D H H VI-247 VI′-247 VI″-247 D H H D DH H VI-248 VI′-248 VI″-248 D H D D D H H VI-249 VI′-249 VI″-249 D D H HH H H VI-250 VI′-250 VI″-250 D D D H H H H VI-251 VI′-251 VI″-251 D D HD H H H VI-252 VI′-252 VI″-252 D D H H D H H VI-253 VI′-253 VI″-253 D DD D H H H VI-254 VI′-254 VI″-254 D D D H D H H VI-255 VI′-255 VI″-255 DD H D D H H VI-256 VI′-256 VI″-256 D D D D D H H VI-257 VI′-257 VI″-257H H H H H H D VI-258 VI′-258 VI″-258 H H D H H H D VI-259 VI′-259VI″-259 H H H D H H D VI-260 VI′-260 VI″-260 H H H H D H D VI-261VI′-261 VI″-261 H H D D H H D VI-262 VI′-262 VI″-262 H H D H D H DVI-263 VI′-263 VI″-263 H H H D D H D VI-264 VI′-264 VI″-264 H H D D D HD VI-265 VI′-265 VI″-265 H D H H H H D VI-266 VI′-266 VI″-266 H D D H HH D VI-267 VI′-267 VI″-267 H D H D H H D VI-268 VI′-268 VI″-268 H D H HD H D VI-269 VI′-269 VI″-269 H D D D H H D VI-270 VI′-270 VI″-270 H D DH D H D VI-271 VI′-271 VI″-271 H D H D D H D VI-272 VI′-272 VI″-272 H DD D D H D VI-273 VI′-273 VI″-273 D H H H H H D VI-274 VI′-274 VI″-274 DH D H H H D VI-275 VI′-275 VI″-275 D H H D H H D VI-276 VI′-276 VI″-276D H H H D H D VI-277 VI′-277 VI″-277 D H D D H H D VI-278 VI′-278VI″-278 D H D H D H D VI-279 VI′-279 VI″-279 D H H D D H D VI-280VI′-280 VI″-280 D H D D D H D VI-281 VI′-281 VI″-281 D D H H H H DVI-282 VI′-282 VI″-282 D D D H H H D VI-283 VI′-283 VI″-283 D D H D H HD VI-284 VI′-284 VI″-284 D D H H D H D VI-285 VI′-285 VI″-285 D D D D HH D VI-286 VI′-286 VI″-286 D D D H D H D VI-287 VI′-287 VI″-287 D D H DD H D VI-288 VI′-288 VI″-288 D D D D D H D VI-289 VI′-289 VI″-289 H H HH H D H VI-290 VI′-290 VI″-290 H H D H H D H VI-291 VI′-291 VI″-291 H HH D H D H VI-292 VI′-292 VI″-292 H H H H D D H VI-293 VI′-293 VI″-293 HH D D H D H VI-294 VI′-294 VI″-294 H H D H D D H VI-295 VI′-295 VI″-295H H H D D D H VI-296 VI′-296 VI″-296 H H D D D D H VI-297 VI′-297VI″-297 H D H H H D H VI-298 VI′-298 VI″-298 H D D H H D H VI-299VI′-299 VI″-299 H D H D H D H VI-300 VI′-300 VI″-300 H D H H D D HVI-301 VI′-301 VI″-301 H D D D H D H VI-302 VI′-302 VI″-302 H D D H D DH VI-303 VI′-303 VI″-303 H D H D D D H VI-304 VI′-304 VI″-304 H D D D DD H VI-305 VI′-305 VI″-305 D H H H H D H VI-306 VI′-306 VI″-306 D H D HH D H VI-307 VI′-307 VI″-307 D H H D H D H VI-308 VI′-308 VI″-308 D H HH D D H VI-309 VI′-309 VI″-309 D H D D H D H VI-310 VI′-310 VI″-310 D HD H D D H VI-311 VI′-311 VI″-311 D H H D D D H VI-312 VI′-312 VI″-312 DH D D D D H VI-313 VI′-313 VI″-313 D D H H H D H VI-314 VI′-314 VI″-314D D D H H D H VI-315 VI′-315 VI″-315 D D H D H D H VI-316 VI′-316VI″-316 D D H H D D H VI-317 VI′-317 VI″-317 D D D D H D H VI-318VI′-318 VI″-318 D D D H D D H VI-319 VI′-319 VI″-319 D D H D D D HVI-320 VI′-320 VI″-320 D D D D D D H VI-321 VI′-321 VI″-321 H H H H H DD VI-322 VI′-322 VI″-322 H H D H H D D VI-323 VI′-323 VI″-323 H H H D HD D VI-324 VI′-324 VI″-324 H H H H D D D VI-325 VI′-325 VI″-325 H H D DH D D VI-326 VI′-326 VI″-326 H H D H D D D VI-327 VI′-327 VI″-327 H H HD D D D VI-328 VI′-328 VI″-328 H H D D D D D VI-329 VI′-329 VI″-329 H DH H H D D VI-330 VI′-330 VI″-330 H D D H H D D VI-331 VI′-331 VI″-331 HD H D H D D VI-332 VI′-332 VI″-332 H D H H D D D VI-333 VI′-333 VI″-333H D D D H D D VI-334 VI′-334 VI″-334 H D D H D D D VI-335 VI′-335VI″-335 H D H D D D D VI-336 VI′-336 VI″-336 H D D D D D D VI-337VI′-337 VI″-337 D H H H H D D VI-338 VI′-338 VI″-338 D H D H H D DVI-339 VI′-339 VI″-339 D H H D H D D VI-340 VI′-340 VI″-340 D H H H D DD VI-341 VI′-341 VI″-341 D H D D H D D VI-342 VI′-342 VI″-342 D H D H DD D VI-343 VI′-343 VI″-343 D H H D D D D VI-344 VI′-344 VI″-344 D H D DD D D VI-345 VI′-345 VI″-345 D D H H H D D VI-346 VI′-346 VI″-346 D D DH H D D VI-347 VI′-347 VI″-347 D D H D H D D VI-348 VI′-348 VI″-348 D DH H D D D VI-349 VI′-349 VI″-349 D D D D H D D VI-350 VI′-350 VI″-350 DD D H D D D VI-351 VI′-351 VI″-351 D D H D D D D VI-352 VI′-352 VI″-352D D D D D D D

TABLE 8 Compounds of Formulae VI, VI′ or VI″, wherein R^(ya) isdeuterium and R^(yb) is hydrogen. Formula Formula Formula R¹/R^(1′)/ R²/R⁷/ R⁸/R^(8′)/ VI VI′ VI″ R^(1″) R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb)VI-353 VI′-353 VI″-353 H H H H H H H VI-354 VI′-354 VI″-354 H H D H H HH VI-355 VI′-355 VI″-355 H H H D H H H VI-356 VI′-356 VI″-356 H H H H DH H VI-357 VI′-357 VI″-357 H H D D H H H VI-358 VI′-358 VI″-358 H H D HD H H VI-359 VI′-359 VI″-359 H H H D D H H VI-360 VI′-360 VI″-360 H H DD D H H VI-361 VI′-361 VI″-361 H D H H H H H VI-362 VI′-362 VI″-362 H DD H H H H VI-363 VI′-363 VI″-363 H D H D H H H VI-364 VI′-364 VI″-364 HD H H D H H VI-365 VI′-365 VI″-365 H D D D H H H VI-366 VI′-366 VI″-366H D D H D H H VI-367 VI′-367 VI″-367 H D H D D H H VI-368 VI′-368VI″-368 H D D D D H H VI-369 VI′-369 VI″-369 D H H H H H H VI-370VI′-370 VI″-370 D H D H H H H VI-371 VI′-371 VI″-371 D H H D H H HVI-372 VI′-372 VI″-372 D H H H D H H VI-373 VI′-373 VI″-373 D H D D H HH VI-374 VI′-374 VI″-374 D H D H D H H VI-375 VI′-375 VI″-375 D H H D DH H VI-376 VI′-376 VI″-376 D H D D D H H VI-377 VI′-377 VI″-377 D D H HH H H VI-378 VI′-378 VI″-378 D D D H H H H VI-379 VI′-379 VI″-379 D D HD H H H VI-380 VI′-380 VI″-380 D D H H D H H VI-381 VI′-381 VI″-381 D DD D H H H VI-382 VI′-382 VI″-382 D D D H D H H VI-383 VI′-383 VI″-383 DD H D D H H VI-384 VI′-384 VI″-384 D D D D D H H VI-385 VI′-385 VI″-385H H H H H H D VI-386 VI′-386 VI″-386 H H D H H H D VI-387 VI′-387VI″-387 H H H D H H D VI-388 VI′-388 VI″-388 H H H H D H D VI-389VI′-389 VI″-389 H H D D H H D VI-390 VI′-390 VI″-390 H H D H D H DVI-391 VI′-391 VI″-391 H H H D D H D VI-392 VI′-392 VI″-392 H H D D D HD VI-393 VI′-393 VI″-393 H D H H H H D VI-394 VI′-394 VI″-394 H D D H HH D VI-395 VI′-395 VI″-395 H D H D H H D VI-396 VI′-396 VI″-396 H D H HD H D VI-397 VI′-397 VI″-397 H D D D H H D VI-398 VI′-398 VI″-398 H D DH D H D VI-399 VI′-399 VI″-399 H D H D D H D VI-400 VI′-400 VI″-400 H DD D D H D VI-401 VI′-401 VI″-401 D H H H H H D VI-402 VI′-402 VI″-402 DH D H H H D VI-403 VI′-403 VI″-403 D H H D H H D VI-404 VI′-404 VI″-404D H H H D H D VI-405 VI′-405 VI″-405 D H D D H H D VI-406 VI′-406VI″-406 D H D H D H D VI-407 VI′-407 VI″-407 D H H D D H D VI-408VI′-408 VI″-408 D H D D D H D VI-409 VI′-409 VI″-409 D D H H H H DVI-410 VI′-410 VI″-410 D D D H H H D VI-411 VI′-411 VI″-411 D D H D H HD VI-412 VI′-412 VI″-412 D D H H D H D VI-413 VI′-413 VI″-413 D D D D HH D VI-414 VI′-414 VI″-414 D D D H D H D VI-415 VI′-415 VI″-415 D D H DD H D VI-416 VI′-416 VI″-416 D D D D D H D VI-417 VI′-417 VI″-417 H H HH H D H VI-418 VI′-418 VI″-418 H H D H H D H VI-419 VI′-419 VI″-419 H HH D H D H VI-420 VI′-420 VI″-420 H H H H D D H VI-421 VI′-421 VI″-421 HH D D H D H VI-422 VI′-422 VI″-422 H H D H D D H VI-423 VI′-423 VI″-423H H H D D D H VI-424 VI′-424 VI″-424 H H D D D D H VI-425 VI′-425VI″-425 H D H H H D H VI-426 VI′-426 VI″-426 H D D H H D H VI-427VI′-427 VI″-427 H D H D H D H VI-428 VI′-428 VI″-428 H D H H D D HVI-429 VI′-429 VI″-429 H D D D H D H VI-430 VI′-430 VI″-430 H D D H D DH VI-431 VI′-431 VI″-431 H D H D D D H VI-432 VI′-432 VI″-432 H D D D DD H VI-433 VI′-433 VI″-433 D H H H H D H VI-434 VI′-434 VI″-434 D H D HH D H VI-435 VI′-435 VI″-435 D H H D H D H VI-436 VI′-436 VI″-436 D H HH D D H VI-437 VI′-437 VI″-437 D H D D H D H VI-438 VI′-438 VI″-438 D HD H D D H VI-439 VI′-439 VI″-439 D H H D D D H VI-440 VI′-440 VI″-440 DH D D D D H VI-441 VI′-441 VI″-441 D D H H H D H VI-442 VI′-442 VI″-442D D D H H D H VI-443 VI′-443 VI″-443 D D H D H D H VI-444 VI′-444VI″-444 D D H H D D H VI-445 VI′-445 VI″-445 D D D D H D H VI-446VI′-446 VI″-446 D D D H D D H VI-447 VI′-447 VI″-447 D D H D D D HVI-448 VI′-448 VI″-448 D D D D D D H VI-449 VI′-449 VI″-449 H H H H H DD VI-450 VI′-450 VI″-450 H H D H H D D VI-451 VI′-451 VI″-451 H H H D HD D VI-452 VI′-452 VI″-452 H H H H D D D VI-453 VI′-453 VI″-453 H H D DH D D VI-454 VI′-454 VI″-454 H H D H D D D VI-455 VI′-455 VI″-455 H H HD D D D VI-456 VI′-456 VI″-456 H H D D D D D VI-457 VI′-457 VI″-457 H DH H H D D VI-458 VI′-458 VI″-458 H D D H H D D VI-459 VI′-459 VI″-459 HD H D H D D VI-460 VI′-460 VI″-460 H D H H D D D VI-461 VI′-461 VI″-461H D D D H D D VI-462 VI′-462 VI″-462 H D D H D D D VI-463 VI′-463VI″-463 H D H D D D D VI-464 VI′-464 VI″-464 H D D D D D D VI-465VI′-465 VI″-465 D H H H H D D VI-466 VI′-466 VI″-466 D H D H H D DVI-467 VI′-467 VI″-467 D H H D H D D VI-468 VI′-468 VI″-468 D H H H D DD VI-469 VI′-469 VI″-469 D H D D H D D VI-470 VI′-470 VI″-470 D H D H DD D VI-471 VI′-471 VI″-471 D H H D D D D VI-472 VI′-472 VI″-472 D H D DD D D VI-473 VI′-473 VI″-473 D D H H H D D VI-474 VI′-474 VI″-474 D D DH H D D VI-475 VI′-475 VI″-475 D D H D H D D VI-476 VI′-476 VI″-476 D DH H D D D VI-477 VI′-477 VI″-477 D D D D H D D VI-478 VI′-478 VI″-478 DD D H D D D VI-479 VI′-479 VI″-479 D D H D D D D VI-480 VI′-480 VI″-480D D D D D D D

In some embodiments, each of R^(xa), R^(xb), R^(ya), and R^(yb) isdeuterium. In some embodiments, each of R^(xa), R^(xb), R^(ya), andR^(yb) is hydrogen. Accordingly, in some embodiments, the presentinvention provides a compound of Formulae VII, VII′ or VII″:

or a pharmaceutically acceptable salt thereof, wherein each of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′),R^(8″), and R⁹, is as defined above and described herein, provided thatat least one of R¹, R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷,R^(7′), R⁸, R^(8′), R^(8″), and R⁹ is deuterium.

In some embodiments of Formulae VII, VII′ or VII″, at least one of R¹,R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R^(7′), R^(7″), R⁸, R^(8″),R^(8″), and R⁹ is deuterium. In some embodiments of Formulae VII, VII′or VII″, the compound is selected from those of Table 13, Table 14, andTable 15:

TABLE 13 Compounds of Formulae VII, VII′ or VII″, wherein each of R³,R^(3′), and R⁴ are deuterium. Formula Formula Formula R¹/R^(1′)/R⁸/R^(8′)/ VII VII′ VII″ R^(1″) R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹ VII-1VII′-1 VII″-1 H H H H H VII-2 VII′-2 VII″-2 H H D H H VII-3 VII′-3VII″-3 H H H D H VII-4 VII′-4 VII″-4 H H H H D VII-5 VII′-5 VII″-5 H H DD H VII-6 VII′-6 VII″-6 H H D H D VII-7 VII′-7 VII″-7 H H H D D VII-8VII′-8 VII″-8 H H D D D VII-9 VII′-9 VII″-9 H D H H H VII-10 VII′-10VII″-10 H D D H H VII-11 VII′-11 VII″-11 H D H D H VII-12 VII′-12VII″-12 H D H H D VII-13 VII′-13 VII″-13 H D D D H VII-14 VII′-14VII″-14 H D D H D VII-15 VII′-15 VII″-15 H D H D D VII-16 VII′-16VII″-16 H D D D D VII-17 VII′-17 VII″-17 D H H H H VII-18 VII′-18VII″-18 D H D H H VII-19 VII′-19 VII″-19 D H H D H VII-20 VII′-20VII″-20 D H H H D VII-21 VII′-21 VII″-21 D H D D H VII-22 VII′-22VII″-22 D H D H D VII-23 VII′-23 VII″-23 D H H D D VII-24 VII′-24VII″-24 D H D D D VII-25 VII′-25 VII″-25 D D H H H VII-26 VII′-26VII″-26 D D D H H VII-27 VII′-27 VII″-27 D D H D H VII-28 VII′-28VII″-28 D D H H D VII-29 VII′-29 VII″-29 D D D D H VII-30 VII′-30VII″-30 D D D H D VII-31 VII′-31 VII″-31 D D H D D VII-32 VII′-32VII″-32 D D D D D

TABLE 14 Compounds of Formulae VII, VII′ or VII″, wherein each of R³ andR^(3′) is deuterium and R⁴ is hydrogen. Formula Formula FormulaR¹/R^(1′)/ R⁸/R^(8′)/ VII VII′ VII″ R^(1″) R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹VII-33 VII′-33 VII″-33 H H H H H VII-34 VII′-34 VII″-34 H H D H H VII-35VII′-35 VII″-35 H H H D H VII-36 VII′-36 VII″-36 H H H H D VII-37VII′-37 VII″-37 H H D D H VII-38 VII′-38 VII″-38 H H D H D VII-39VII′-39 VII″-39 H H H D D VII-40 VII′-40 VII″-40 H H D D D VII-41VII′-41 VII″-41 H D H H H VII-42 VII′-42 VII″-42 H D D H H VII-43VII′-43 VII″-43 H D H D H VII-44 VII′-44 VII″-44 H D H H D VII-45VII′-45 VII″-45 H D D D H VII-46 VII′-46 VII″-46 H D D H D VII-47VII′-47 VII″-47 H D H D D VII-48 VII′-48 VII″-48 H D D D D VII-49VII′-49 VII″-49 D H H H H VII-50 VII′-50 VII″-50 D H D H H VII-51VII′-51 VII″-51 D H H D H VII-52 VII′-52 VII″-52 D H H H D VII-53VII′-53 VII″-53 D H D D H VII-54 VII′-54 VII″-54 D H D H D VII-55VII′-55 VII″-55 D H H D D VII-56 VII′-56 VII″-56 D H D D D VII-57VII′-57 VII″-57 D D H H H VII-58 VII′-58 VII″-58 D D D H H VII-59VII′-59 VII″-59 D D H D H VII-60 VII′-60 VII″-60 D D H H D VII-61VII′-61 VII″-61 D D D D H VII-62 VII′-62 VII″-62 D D D H D VII-63VII′-63 VII″-63 D D H D D VII-64 VII′-64 VII″-64 D D D D D

TABLE 15 Compounds of Formulae VII, VII′ or VII″, wherein each of R³ andR^(3′) is hydrogen and R⁴ is deuterium. Formula Formula FormulaR¹/R^(1′)/ R⁸/R^(8′)/ VII VII′ VII″ R^(1″) R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹VII-65 VII′-65 VII″-65 H H H H H VII-66 VII′-66 VII″-66 H H D H H VII-67VII′-67 VII″-67 H H H D H VII-68 VII′-68 VII″-68 H H H H D VII-69VII′-69 VII″-69 H H D D H VII-70 VII′-70 VII″-70 H H D H D VII-71VII′-71 VII″-71 H H H D D VII-72 VII′-72 VII″-72 H H D D D VII-73VII′-73 VII″-73 H D H H H VII-74 VII′-74 VII″-74 H D D H H VII-75VII′-75 VII″-75 H D H D H VII-76 VII′-76 VII″-76 H D H H D VII-77VII′-77 VII″-77 H D D D H VII-78 VII′-78 VII″-78 H D D H D VII-79VII′-79 VII″-79 H D H D D VII-80 VII′-80 VII″-80 H D D D D VII-81VII′-81 VII″-81 D H H H H VII-82 VII′-82 VII″-82 D H D H H VII-83VII′-83 VII″-83 D H H D H VII-84 VII′-84 VII″-84 D H H H D VII-85VII′-85 VII″-85 D H D D H VII-86 VII′-86 VII″-86 D H D H D VII-87VII′-87 VII″-87 D H H D D VII-88 VII′-88 VII″-88 D H D D D VII-89VII′-89 VII″-89 D D H H H VII-90 VII′-90 VII″-90 D D D H H VII-91VII′-91 VII″-91 D D H D H VII-92 VII′-92 VII″-92 D D H H D VII-93VII′-93 VII″-93 D D D D H VII-94 VII′-94 VII″-94 D D D H D VII-95VII′-95 VII″-95 D D H D D VII-96 VII′-96 VII″-96 D D D D D

In some embodiments, each of each of R³, R^(3′), R⁴, R^(xa), R^(xb),R^(ya), and R^(yb) is deuterium. Accordingly, in some embodiments, thepresent invention provides a compound of Formulae VIII, VIII′ or VIII″:

In some embodiments of Formulae VIII, VIII′ or VIII″, the compound isselected from those of Table 16:

TABLE 16 Compounds of Formulae VIII, VIII′ or VIII″. Formula FormulaFormula R¹/R^(1′)/ R⁸/R^(8′)/ VIII VIII′ VIII″ R^(1″) R²/R^(2′)R⁷/R^(7′) R^(8″) R⁹ VIII-1 VIII′-1 VIII″-1 H H H H H VIII-2 VIII′-2VIII″-2 H H D H H VIII-3 VIII′-3 VIII″-3 H H H D H VIII-4 VIII′-4VIII″-4 H H H H D VIII-5 VIII′-5 VIII″-5 H H D D H VIII-6 VIII′-6VIII″-6 H H D H D VIII-7 VIII′-7 VIII″-7 H H H D D VIII-8 VIII′-8VIII″-8 H H D D D VIII-9 VIII′-9 VIII″-9 H D H H H VIII-10 VIII′-10VIII″-10 H D D H H VIII-11 VIII′-11 VIII″-11 H D H D H VIII-12 VIII′-12VIII″-12 H D H H D VIII-13 VIII′-13 VIII″-13 H D D D H VIII-14 VIII′-14VIII″-14 H D D H D VIII-15 VIII′-15 VIII″-15 H D H D D VIII-16 VIII′-16VIII″-16 H D D D D VIII-17 VIII′-17 VIII″-17 D H H H H VIII-18 VIII′-18VIII″-18 D H D H H VIII-19 VIII′-19 VIII″-19 D H H D H VIII-20 VIII′-20VIII″-20 D H H H D VIII-21 VIII′-21 VIII″-21 D H D D H VIII-22 VIII′-22VIII″-22 D H D H D VIII-23 VIII′-23 VIII″-23 D H H D D VIII-24 VIII′-24VIII″-24 D H D D D VIII-25 VIII′-25 VIII″-25 D D H H H VIII-26 VIII′-26VIII″-26 D D D H H VIII-27 VIII′-27 VIII″-27 D D H D H VIII-28 VIII′-28VIII″-28 D D H H D VIII-29 VIII′-29 VIII″-29 D D D D H VIII-30 VIII′-30VIII″-30 D D D H D VIII-31 VIII′-31 VIII″-31 D D H D D VIII-32 VIII′-32VIII″-32 D D D D D

In some embodiments, the present invention provides compounds comprisingone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, or eighteendeuterium atoms. In some embodiments, provided compounds comprisedeuterium in an amount of about 6%, or about 11%, or about 17%, or about22%, or about 28%, or about 33%, or about 39%, or about 44%, or about50%, or about 56%, or about 61%, or about 67%, or about 72%, or about78%, or about 83%, or about 89%, or about 94%, or about 100%. In someembodiments, the present invention provides deuterium-enriched compoundsaccording to Table 17:

TABLE 17 Deuterium Enriched Compounds of Formula I, I′ or I″. Number ofPercent Deuterium Atoms Enrichment 1 5.6 2 11.1 3 16.7 4 22.2 5 27.8 633.3 7 38.9 8 44.4 9 50.0 10 55.6 11 61.1 12 66.7 13 72.2 14 77.8 1583.3 16 88.9 17 94.4 18 100

In some embodiments, the present invention provides a compound selectedfrom any of Tables 1-16 above, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present inventions provides a compound selectedfrom any of those depicted below:

In some embodiments, the present inventions provides a compound selectedfrom any of those depicted below:

In some embodiments, the present invention provides an isolated orpurified compound of any of Formulae I, I′, I″, II, II′, II″, III, III′,III″, IV, IV′, IV″, V, V′, V″, VI, VI′, VI″, VII, VII′, VII″, VIII,VIII′, or VIII″. In some embodiments of any of Formulae I, I′, II, II′,III, III′, V, V′, VII, or VII′, the compound is other than:

Compounds of Formulae I, I′, I″, II, II′, II″, III, III′, III″, IV, IV′,IV″, V, V′, V″, VI, VI′, VI″, VII, VII′, VII″, VIII, VIII′, or VIII″contain a chloropyrimidine moiety which is capable of and particularlysuitable for covalently binding to a key cysteine residue in the bindingdomain of MK2. In certain embodiments, compounds of the presentinvention having a chloropyrimidine group target Cys140 of MK2. Incertain embodiments, Cys140 of MK2 is characterized in that Cys140 isthe cysteine embedded in the following amino acid sequence of MK2:

SEQ ID NO. 1: MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGRKCLLIVME C LDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQYLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKEEMTSALATMRVDYEQIKIKKIEDASNPLLLKRRKKARALEAAALAH.

For the purpose of clarity, Cys140 is provided in the abbreviated aminoacid sequence below:

SEQ ID NO. 2: NLYAGRKCLLIVME C(140) LDGGELFSRIQDR.

In both SEQ ID NOS. 1 and 2, Cysteine 140 is highlighted in bold withunderlining.

Thus, in some embodiments, compounds of the present invention having achloropyrimidine group are capable of covalently binding to a cysteineresidue of MK2, thereby irreversibly inhibiting the enzyme. In someembodiments, the cysteine residue is Cys140.

In some embodiments, provided compounds are irreversible inhibitors ofMK2, or a mutant thereof, and therefore useful for treating one ordisorders as described herein.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier, adjuvant, orvehicle. In certain embodiments, the amount of compound in compositionsof this invention is such that it is effective to measurably inhibitMK2, or a mutant thereof, in a biological sample or in a patient. Incertain embodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

Compounds and compositions, according to method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided herein (i.e., an MK2-mediated disease or disorder).The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. Compounds of the invention are preferably formulated in unitdosage form for ease of administration and uniformity of dosage.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally, intraperitoneally, intracisternally or via animplanted reservoir. In some embodiments, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

In some embodiments, provided pharmaceutically acceptable compositionsare formulated for oral administration. Such formulations may beadministered with or without food. In some embodiments, pharmaceuticallyacceptable compositions of this invention are administered without food.In other embodiments, pharmaceutically acceptable compositions of thisinvention are administered with food. Pharmaceutically acceptablecompositions of this invention may be orally administered in any orallyacceptable dosage form including, but not limited to, capsules, tablets,aqueous suspensions or solutions. In the case of tablets for oral use,carriers commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried cornstarch. When aqueous suspensions are required for oral use,the active ingredient is combined with emulsifying and suspendingagents. If desired, certain sweetening, flavoring or coloring agents mayalso be added.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and/or i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of kinase activity of one or more enzymes. Examples ofkinases that are inhibited by the compounds and compositions describedherein and against which the methods described herein are useful includeMK2, or a mutant thereof.

The activity of a compound utilized in this invention as an inhibitor ofa MK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo orin a cell line. In vitro assays include assays that determine inhibitionof either the phosphorylation activity and/or the subsequent functionalconsequences, or ATPase activity of activated MK2 kinase, or a mutantthereof. Alternate in vitro assays quantitate the ability of the testcompound to bind to MK2. Inhibitor binding may be measured byradiolabeling the test compound prior to binding, isolating the testcompound/MK2 complex and determining the amount of radiolabel bound.Alternatively, inhibitor binding may be determined by running acompetition experiment where test compounds are incubated with MK2kinase bound to known radioligands. Detailed conditions for assaying acompound utilized in this invention as an inhibitor of MK2, or a mutantthereof, are set forth in the Examples, below.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting MK2 kinase, or a mutant thereof, activity in a biologicalsample comprising the step of contacting said biological sample with acompound of this invention, or a composition comprising said compound.In certain embodiments, the invention relates to a method ofirreversibly inhibiting MK2 kinase, or a mutant thereof, activity in abiological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting MK2 kinase, or a mutant thereof, activity in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method ofirreversibly inhibiting MK2 kinase, or a mutant thereof, activity in apatient comprising the step of administering to said patient a compoundof the present invention, or a composition comprising said compound. Inother embodiments, the present invention provides a method for treatingan MK2-mediated disease or disorder, in a patient in need thereof,comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

MK2 Kinase

MAP kinase-activated protein kinase 2 (“MK2”) is an enzyme that inhumans is encoded by the MAPKAPK2 gene. The MAPKAPK2 gene encodes amember of the Ser/Thr protein kinase family and two transcript variantsencoding two different isoforms have been found. MK2 is regulatedthrough direct phosphorylation by p38 MAP kinase.

MK2 is a multi-domain protein consisting of an N-terminal proline-richdomain, a catalytic domain, an autoinhibitory domain and at theC-terminus a nuclear export signal (NES) and nuclear localization signal(NLS). Two isoforms of human MK2 have been characterized. One isoformconsists of 400 amino acids and the other isoform 370 residues which isthought to be a splice variant missing the C-terminal NLS.

MK2 is known to be involved in many cellular processes including stressand inflammatory responses, nuclear export, gene expression regulationand cell proliferation. Indeed, MK2 regulates, by a post-transcriptionalmechanism, biosynthesis of tumor necrosis factor α (TNFα) that isoverproduced in inflammatory diseases such as rheumatoid arthritis andinflammatory bowel disease. See Natesan et al., J. Med. Chem. 2012, 55,2035-2047.

Inhibition of Hsp27 phosphorylation occurs by inhibiting the formationof the p38 kinase-MK2-Hsp27 signaling complex. Phosphorylation of Hsp27is the penultimate event in a complex signaling cascade that occurs inresponse to extracellular stimuli. See Zheng et al., The Journal ofBiological Chemistry, vol. 281, no. 48, 37215-37226, Dec. 1, 2006. Hsp27usually exists as oligomers and plays a role in regulation of manycellular functions such as inhibition of the death receptor-mediatedapoptosis, promotion of proper refolding of denatured proteins by actingas a molecular chaperone, and regulation of cytoskeleton. The presenceof MK2 is a necessary condition for the formation of p38kinase-MK2-Hsp27 signaling complex in cells. See Zheng et al., TheJournal of Biological Chemistry, vol. 281, no. 48, 37215-37226, Dec. 1,2006.

Evidence suggests that many signaling proteins form multimericcomplexes. See Zheng et al., The Journal of Biological Chemistry, vol.281, no. 48, 37215-37226, Dec. 1, 2006. One such complex is theHsp27/Akt (a serine/threonine kinase) dimer, which forms in thecytoplasm of a cell. Another complex is formed between MK2 and p38. SeeBen-Levy et al., Current Biology 1998, 8:1049-1057; Natesan et al., J.Med. Chem. 2012, 55, 2035-2047; Zheng et al., The Journal of BiologicalChemistry, vol. 281, no. 48, 37215-37226, Dec. 1, 2006.

In unstimulated conditions, inactive p38 and unphosphorylated MK2 formsuch dimer in the nucleus of a cell. Upon activation, p38 phosphorylatesMK2, thereby inducing a conformational change of the autoinhibitorydomain of MK2 and exposing the active site for substrate binding. OnceMK2 is phosphorylated, the p38-MK2 dimer is translocated to thecytoplasm, where it forms a quaternary complex with the Hsp27-Akt dimer.See Zheng et al., The Journal of Biological Chemistry, vol. 281, no. 48,37215-37226, Dec. 1, 2006. Hsp27 is then phosphorylated by MK2,resulting in degradation of the quaternary complex and the release ofp-Hsp27 monomers and dimers. Because inhibition of MK2 blocksphosphorylation of Hsp27, without wishing to be bound by theory, it isbelieved that inhibition of MK2 prevents degradation of thep38-MK2-Akt-Hsp27 quaternary complex, thereby altering downstreameffects. Consequent to the inhibition of quaternary complex degradation,the amount of quaternary complex would thereby increase. Moreover, theequilibrium of p38 and MK2 between the cytoplasm and nucleus would beshifted towards the cytoplasm.

Interestingly, transport of the MK2/p38 complex out of the nucleus doesnot require catalytically active MK2, as the active site mutant,Asp207Ala, is still transported to the cytoplasm. Phosphorylation ofhuman MK2 by p38 on residues T222, S272 and T334 is thought to activatethe enzyme by inducing a conformational change of the autoinhibitorydomain thus exposing the active site for substrate binding. Mutations oftwo autoinhibitory domain residues W332A and K326E in murine MK2demonstrate an increase in basal activity and a C-terminal deletion ofthe autoinhibitory domain renders the enzyme constitutively active,providing additional evidence to the role of this domain in inhibitionof MK2 activity.

Diseases or disorders associated with MK2 that are treated by compoundsof the present invention include autoimmune disorders, chronicinflammatory disorders, acute inflammatory disorders, auto-inflammatorydisorders, fibrotic disorders, metabolic disorders, neoplasias, orcardiovascular or cerebrovascular disorders. Thus, in some embodiments,the present invention provides a method for treating an MK2-mediateddisease or disorder in a patient in need thereof, wherein said methodcomprises administering to said patient a therapeutically effectiveamount of a provided compound, or composition thereof. Such MK2-mediateddiseases or disorders include, but are not limited to those describedherein.

In some embodiments, the MK2-mediated disease or disorder is anautoimmune disorder, chronic and/or acute inflammatory disorder, and/orauto-inflammatory disorder. Exemplary autoimmune and/or inflammatoryand/or auto-inflammatory disorders include: inflammatory bowel diseases(for example, ulcerative colitis or Crohn's disease), multiplesclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis,juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosingspondylitis, cryopyrin associated periodic syndromes, Muckle-Wellssyndrome, familial cold auto-inflammatory syndrome, neonatal-onsetmultisystem inflammatory disease, TNF receptor associated periodicsyndrome, acute and chronic pancreatitis, atherosclerosis, gout,ankylosing spondylitis, fibrotic disorders (for example, hepaticfibrosis or idiopathic pulmonary fibrosis), nephropathy, sarcoidosis,scleroderma, anaphylaxis, diabetes (for example, diabetes mellitus type1 or diabetes mellitus type 2), diabetic retinopathy, Still's disease,vasculitis, sarcoidosis, pulmonary inflammation, acute respiratorydistress syndrome, wet and dry age-related macular degeneration,autoimmune hemolytic syndromes, autoimmune and inflammatory hepatitis,autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis,autoimmune thrombocytopenia, silicone implant associated autoimmunedisease, Sjogren's syndrome, familial Mediterranean fever, systemiclupus erythematosus, vasculitis syndromes (for example, temporal,Takayasu's and giant cell arteritis, Behget's disease or Wegener'sgranulomatosis), vitiligo, secondary hematologic manifestation ofautoimmune diseases (for example, anemias), drug-induced autoimmunity,Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic pupura,metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmunedeafness (for example, Meniere's disease), Goodpasture's syndrome,Graves' disease, HW-related autoimmune syndromes, Guillian-Barredisease, Addison's disease, anti-phospholipid syndrome, asthma, atopicdermatitis, Celiac disease, Cushing's syndrome, dermatomyositis,idiopathic adrenal adrenal atrophy, idiopathic thrombocytopenia,Kawasaki syndrome, Lambert-Eaton Syndrome, pernicious anemia,pollinosis, polyarteritis nodosa, primary biliary cirrhosis, primarysclerosing cholangitis, Raynaud's, Reiter's Syndrome, relapsingpolychondritis, Schmidt's syndrome, thyrotoxidosis, sepsis, septicshock, endotoxic shock, exotoxin-induced toxic shock, gram negativesepsis, toxic shock syndrome, glomerulonephritis, peritonitis,interstitial cystitis, hyperoxia-induced inflammations, chronicobstructive pulmonary disease (COPD), vasculitis, graft vs. hostreaction (for example, graft vs. host disease), allograft rejections(for example, acute allograft rejection or chronic allograft rejection),early transplantation rejection (for example, acute allograftrejection), reperfusion injury, pain (for example, acute pain, chronicpain, neuropathic pain, or fibromyalgia), chronic infections,meningitis, encephalitis, myocarditis, gingivitis, post surgical trauma,tissue injury, traumatic brain injury, enterocolitis, sinusitis,uveitis, ocular inflammation, optic neuritis, gastric ulcers,esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis,myositis, polymyalgia, pneumonia and bronchitis.

In some embodiments, the MK2-mediated disease or disorder is a fibroticdisorder. Exemplary fibrotic disorders include systemicsclerosis/scleroderma, lupus nephritis, connective tissue disease, woundhealing, surgical scarring, spinal cord injury, CNS scarring, acute lunginjury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosisor cystic fibrosis), chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension-induced nephropathy, alimentarytrack or gastrointestinal fibrosis, renal fibrosis, hepatic or biliaryfibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis,hepatitis C, or hepatocellular carcinoma), cirrhosis (for example,primary biliary cirrhosis or cirrhosis due to fatty liver disease (forexample, alcoholic and nonalcoholic steatosis)), radiation-inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),primary sclerosing cholangitis, restenosis, cardiac fibrosis (forexample, endomyocardial fibrosis or atrial fibrosis), opthalmicscarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma,fibroadenomas, fibrosarcomas, transplant arteriopathy, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, and nephrogenic systemic fibrosis.

In some embodiments, the MK2-mediated disease or disorder is a metabolicdisorder. Exemplary metabolic disorders include obesity,steroid-resistance, glucose intolerance, and metabolic syndrome.

In some embodiments, the MK2-mediated disease or disorder is aneoplasia. Exemplary neoplasias include cancers. In some embodiments,exemplary neoplasias include angiogenesis disorders, multiple myeloma,leukemias (for example, acute lymphocytic leukemia, acute and chronicmyelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, or promyelocytic leukemia), lymphomas (for example, B-celllymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma,Burkitt's lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin'sdisease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma,thyroid follicular cancer, Kaposi's sarcoma, melanoma, teratoma,rhabdomyosarcoma, metastatic and bone disorders, as well as cancer ofthe bone, mouth/pharynx, esophagus, larynx, stomach, intestine, colon,rectum, lung (for example, non-small cell lung cancer or small cell lungcancer), liver, pancreas, nerve, brain (for example, glioma orglioblastoma multiforme), head and neck, throat, ovary, uterus,prostate, testis, bladder, kidney, breast, gall bladder, cervix,thyroid, prostate, and skin.

In some embodiments, the MK2-mediated disorder is a cardiovascular orcerebrovascular disorder. Exemplary cardiovascular disorders includeatherosclerosis, restenosis of an atherosclerotic coronary artery, acutecoronary syndrome, myocardial infarction, cardiac-allograft vasculopathyand stroke. Exemplary cerebrovascular diseases include central nervoussystem disorders with an inflammatory or apoptotic component,Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia andperipheral neuropathy.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Table of abbreviations. TFA trifluoroacetic acid TLC thin layerchromatography THF tetrahydrofuran DMF N,N-dimethylformamide EA ethylacetate DMSO dimethylsulfoxide m-CPBA m-chloroperoxybenzoic acid DMAP4-dimethylaminopyridine MeOH methanol PE petroleum ether h hour minsminutes

Example 1

Preparation of Deuterated Intermediate 1 (INT-1).

Deuterated intermediate 1 (INT-1) was prepared according to Scheme 1below:

Synthesis of 2-aminopropan-1,1,2,3,3,3-d₆-1-ol (S1-2)

To a stirred solution of alanine-2,3,3,3-d₄ (S1-1) (1.0 g, 10.7 mmol) inTHE (30 mL) was added LiAlD₄ (902.0 mg, 21.5 mmol) at 0° C. Uponcomplete addition, the resulting suspension was stirred under reflux for3 h. TLC showed the reaction was complete and was followed by slowaddition of water to quench excess LiAlD₄. The resulting mixturecontaining 2-aminopropan-1,1,2,3,3,3-d₆-1-ol (S1-2) was used directlyfor next step.

Synthesis of tert-butyl (1-hydroxypropan-2-yl-1,1,2,3,3,3-d₆)carbamate(S1-3)

To the above suspension containing 2-aminopropan-1,1,2,3,3,3-d₆-1-ol(S1-2) was added saturated aqueous Na₂CO₃ (10 mL) to adjust pH value to˜10-13 at 0° C. Boc₂O (3.0 g, 14.0 mmol) was added and stirred at roomtemperature overnight. TLC showed the reaction was complete and thereaction mixture was diluted with ethyl acetate (20 mL) and water (20mL). The organic layer was separated and the aqueous layer was extractedwith ethyl acetate (2×20 mL). The combined organic extracts were driedover sodium sulfate, filtered, and concentrated. Purification by flashcolumn chromatography on silica gel (eluent:PE:EA 1:1) to affordtert-butyl (1-hydroxypropan-2-yl-1,1,2,3,3,3-d₆)carbamate (S1-3) (1.7 g,87.5% over two steps) as a light-yellow oil.

Synthesis of tert-butyl4-(methyl-d₃)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d₃ 2-oxide(S1-4)

To a stirred suspension of imidazole (3.9 g, 56.7 mmol) indichloromethane (17 mL) was added a solution of thionyl chloride (1.2mL, 17 mmol) in dichloromethane (12 mL) at 0° C. dropwise over 0.5 h.The resulting mixture was stirred at room temperature for 1 h followedby addition of a solution of tert-butyl(1-hydroxypropan-2-yl-1,1,2,3,3,3-d₆)carbamate (S1-3) (1.7 g, 9.4 mmol)in dichloromethane (17 mL) dropwise 0° C. The cooling bath was removedand the reaction mixture was stirred at room temperature for 10 mins.Aqueous citric acid (68 mL, 10 w/w %) was added and stirred for 15 min.The organic phase was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and filtered and concentrated. The mixture waspurified by column chromatography (eluent:PE:EA 5:1) to obtaintert-butyl 4-(methyl-d₃)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d₃2-oxide (S1-4) (1.7 g, 79.8%) as a colorless oil. ¹H NMR: (300 MHz,CDCl₃) δ 1.53 (s, 9H).

Synthesis of tert-butyl4-(methyl-d₃)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d₃ 2,2-dioxide(S1-5)

To a solution of tert-butyl4-(methyl-d₃)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d₃ 2-oxide(S1-4) (1.7 g, 7.5 mmol) in acetonitrile (28 L) was added RuCl₃ (0.84mg, 0.004 mmol) followed by a solution of NaIO₄ (1.6 g, 7.5 mmol) inwater (16 mL). The reaction mixture was stirred at room temperature for40 mins and then diluted by addition of dichloromethane (30 mL) andwater (30 mL). The organic phase was separated, washed with brine, driedover anhydrous sodium sulfate, and concentrated. The mixture waspurified by column chromatography (eluent:PE:EA 3:1) to obtaintert-butyl 4-(methyl-d₃)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d₃2,2-dioxide (S1-5) (1.6 g, 87.9%) as a white solid. ¹H NMR: (300 MHz,CDCl₃) δ 1.56 (s, 9H).

Synthesis of methyl1-((2-((tert-butoxycarbonyl)amino)propyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylate(S1-6)

Methyl1-((2-((tert-butoxycarbonyl)amino)propyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylate(S1-6) was prepared according to the following scheme:

To a solution of methyl 1-aminothieno[3,2-f]quinoline-2-carboxylate(S1-14) (1.5 g, 5.8 mmol) in dry DMF (58 mL) at 0° C. was added NaH (60%in mineral oil, 278.2 mg, 7.0 mmol) portion wise over 0.5 h undernitrogen. The mixture was stirred at 0° C. for another 0.5 h followed byaddition of tert-butyl4-(methyl-d₃)-1,2,3-oxthiazolidine-3-carboxylate-4,5,5-d₃ 2,2-dioxide(S1-5) (1.4 g, 5.8 mmol) in portions over 0.5 h. Upon complete addition,TLC analysis showed that the starting material was fully consumed andformation of a less polar spot. Water (21 mL) was slowly added to theabove mixture followed by aqueous HCl (1 M, 21 mL, 21 mmol). The mixturewas extracted with 10% MeOH in dichloromethane, and the organic layerwas separated. The aqueous layer was extracted 10% MeOH indichloromethane (2×50 mL), and the combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated to give thecrude material. Purification by column chromatography on silica gel(eluent: dichloromethane:MeOH 20:1) afforded methyl1-((2-((tert-butoxycarbonyl)amino)propyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylate(S1-6) (2.4 g, 90.4%) as a brown oil. MS m/z (M+H): 422.3.

Synthesis of methyl1-((2-aminopropyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylate(S1-7)

Methyl1-((2-((tert-butoxycarbonyl)amino)propyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylate(S1-6) (1.8 g, 4.3 mmol) was suspended in a stirred solution of HCl (4 Min 1,4-dioxane, 20 mL) at room temperature for 1 h. LCMS showed thereaction was complete. The resulting suspension was concentrated underreduced pressure to afford methyl1-((2-aminopropyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylate(S1-7) as hydrochloride salt as a yellow solid, which was used in nextstep without further purification. MS m/z (M+H): 322.2.

Synthesis of10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(S1-8)

To a suspension of methyl1-((2-aminopropyl-1,1,2,3,3,3-d₆)amino)thieno[3,2-f]quinoline-2-carboxylatehydrochloride (S1-7) in MeOH (60 mL) was added NaOMe (1.7 g, 30.7 mmol)at room temperature. The reaction mixture was heated at 70° C. for 3 h.LCMS and TLC showed the reaction was complete and the reaction mixturewas concentrated to afford crude compound. Purification by columnchromatography on silica gel (eluent:dichloromethane:MeOH 20:1) toafford10-(methyl-d)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(S1-8) (852 mg, 68.6% over two steps) as a yellow solid. MS m/z (M+H):290.2.

Synthesis of di-tert-butyl10-(methyl-d₃)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate-10,11,11-d₃(S1-9)

To a solution of10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(S1-8) (1.9 g, 6.6 mmol) in dichloromethane (42 mL) were added DMAP(200.7 mg, 1.6 mmol) and triethylamine (2.3 mL, 16.5 mmol). The mixturewas stirred at room temperature for 10 mins followed by addition ofBoc₂O (7.2 g, 32.9 mmol). The reaction mixture was stirred at roomtemperature overnight. TLC showed the reaction was complete andconcentrated to give crude compound. Purification by columnchromatography on silica gel (eluent:PE:EA 5:1) to afford productdi-tert-butyl10-(methyl-d₃)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate-10,11,11-d₃(S1-9) (2.7 g, 83.8%) as a white solid. MS m/z (M+H): 490.3.

Synthesis of9,12-bis(tert-butoxycarbonyl)-10-(methyl-d₃)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline4-oxide-10,11,11-d₃ (S1-10)

To solution of di-tert-butyl10-(methyl-d₃)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate-10,11,11-d₃(S1-9) (1.7 g, 3.5 mmol) in dichloromethane (30 mL) at 0° C. was chargedwith m-CPBA (1.2 g, 7.0 mmol) in portions. The reaction mixture wasstirred at room temperature for 3 h. TLC showed the fully consumption ofstarting material. Aqueous Na₂SO₃ (20 mL, 5 w/w %) was added to quenchexcess oxidants. The organic phase was separated followed by saturatedaqueous NaHCO₃ and brine wash, dried over anhydrous sodium sulfate,filtered, and concentrated to afford9,12-bis(tert-butoxycarbonyl)-10-(methyl-d)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline4-oxide-10,11,11-d₃ (S1-10) as a yellow solid, which was used in thenext step without further purification. MS m z (M+H): 506.4.

Synthesis of di-tert-butyl3-chloro-10-(methyl-d₃)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate-10,11,11-d₃(S1-11)

9,12-bis(tert-butoxycarbonyl)-10-(methyl-d₃)-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline4-oxide-10,11,11-d₃ (S1-10) was dissolved in DMF (10 mL), and themixture was cooled to 0° C. (COCl)₂ (192.0 mg, 1.5 mmol) was added over1 h and stirred at room temperature for 1 h. TLC showed the reaction wascomplete. Water (30 mL) was added 0° C. and extracted with ethyl acetate(3×30 mL). The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated. Purification by columnchromatography on silica gel (eluent:PE:EA 3:1) afforded di-tert-butyl3-chloro-10-(methyl-d₃)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate-10,11,11-d₃(S1-11) (966 mg, 53.5%) as a white solid. MS m/z (M+H): 524.4.

Synthesis of3-chloro-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(S1-12)

To a solution of di-tert-butyl3-chloro-10-(methyl-d₃)-8-oxo-10,11-dihydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinoline-9,12-dicarboxylate-10,11,11-d₃(S1-11) (966.0 mg, 1.8 mmol) in dichloromethane (6 mL) and TFA (2 mL)was added dropwise at 0° C. The resulting reaction mixture was stirredat room temperature for 2 h. After completion, the reaction mixture wasconcentrated under reduced pressure to afford3-chloro-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(S1-12) as a brown oil, which was used in the next step without furtherpurification. MS m/z (M+H): 324.2

Synthesis of3-hydroxy-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(INT-1)

Into a 25 mL round-bottom flask with acetic acid (12 mL) and water (6mL) was added3-chloro-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(S-12). The resulting suspension mixture was stirred at 110° C. for 24hours to yield a brown solution. The resulting solution was cooled andconcentrated to remove most of the solvent. Saturated ammonium hydroxide(2.0 g) was added to the residue, and precipitation was observed.Further stirring at room temperature for 1 h and filtration afforded ayellow solid. The filter cake was washed with water (3.6 mL) and driedunder vacuum. The crude product was slurred with ethyl acetate (3.6 ml)for 1 hour and filtered. The solid was washed with ethyl acetate (3.6mL), dried under vacuum at 55° C. to afford3-hydroxy-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(INT-1) (880 mg, 97.4%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.1 (brs, 1H),8.77 (d, J=9.0 Hz, 1H), 8.03 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.40 (d,J=9.0 Hz, 1H), 6.80 (s, 1H), 6.57 (d, J=9.0 Hz, 1H). MS m/z (M+H):306.2.

Example 2 Preparation of3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(I-2)

3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-(methyl-d)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(I-2) was prepared according to Scheme 2 below.

To a stirred solution of3-hydroxy-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(INT-1) (200.0 mg, 0.6 mmol) in DMSO (4 mL) was added K₂CO₃ (180.8 mg,1.3 mmol) and stirred at room temperature for 40 mins followed byaddition of 2,4-dichloro-5-(ethoxymethyl)pyrimidine (203.4 mg, 1.0mmol). This reaction mixture was stirred at room temperature overnight.LCMS showed the reaction was complete. The reaction mixture was passedthough silica gel and purified by reverse phase prep-HPLC to afford3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-(methyl-d₃)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one-10,11,11-d₃(I-2) (111.1 mg, 39.0%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.36 (d, J=9.0 Hz, 1H), 8.71 (s, 1H), 8.19 (s, J=9.0 Hz, 1H), 8.12 (s,1H), 7.86 (d, J=9.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 4.66 (s, 1H), 3.62(dd, J=4.0 Hz, 2H), 1.20 (t, J=4.0 Hz, 3H). MS m/z (M+H): 476.3.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

ENUMERATED EMBODIMENTS

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each of R¹, R^(1′), R^(1″), R², R^(2′), R³, R^(3′), R⁴, R⁷,        R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa), R^(xb), R^(ya), and        R^(yb) is independently selected from hydrogen or deuterium;    -   provided that at least one of R¹, R^(1′), R^(1″), R², R^(2′),        R³, R^(3′), R⁴, R⁷, R^(7′), R⁸, R^(8′), R^(8″), R⁹, R^(xa),        R^(xb), R^(ya), and R^(yb) is deuterium.        2. The compound according to embodiment 1, wherein the compound        is of Formulae I′ or I″:

or a pharmaceutically acceptable salt thereof.3. The compound according to embodiments 1 or 2, wherein R¹, R^(1′),R^(1″) are the same.4. The compound according to embodiments 1 or 2, wherein R², R^(2′) arethe same.5. The compound according to any of embodiments 1-4, wherein each of R¹,R^(1′), R^(1′) is deuterium.6. The compound according to any of embodiments 1-5, wherein each of R²,R^(2′) is deuterium.7. The compound according to any of embodiments 1, 3, or 4, wherein eachof R¹, R^(1′), R^(1″) is hydrogen.8. The compound according to any of embodiments 1, 3, 4, or 5, whereineach of R², R^(2′) is hydrogen.9. The compound according to any of embodiments 1-8, wherein R⁷ andR^(7′) are the same.10. The compound according to any of embodiments 1-9, wherein R⁸, R^(8′)and R^(8″) are the same.11. The compound according to any of embodiments 1-10, wherein each ofR⁷ and R^(7′) is deuterium.12. The compound according to any of embodiments 1-11, wherein each ofR⁸, R^(8′) and R^(8″) is deuterium.13. The compound according to any of embodiments 1-12, wherein R⁹ isdeuterium.14. The compound according to any of embodiments 1-10, wherein each ofR⁷ and R^(7′) is hydrogen.15. The compound according to any of embodiments 1-10 or 14, whereineach of R⁸, R^(8′), and R^(8″) is hydrogen.16. The compound according to any of embodiments 1-10, 14, or 15,wherein R⁹ is hydrogen.17. The compound according to any of embodiments 1-16, wherein each ofR³ and R^(3′) is hydrogen.18. The compound according to any of embodiments 1-16, wherein each ofR³ and R^(3′) is deuterium.19. The compound according to any of embodiments 1-18, wherein R⁴ ishydrogen.20. The compound according to any of embodiments 1-18, wherein R⁴ isdeuterium.21. The compound according to any of embodiments 1-20, wherein each ofR^(xa) and R^(xb) is hydrogen.22. The compound according to any of embodiments 1-20, wherein each ofR^(xa) and R^(b) is deuterium.23. The compound according to any of embodiments 1-22, wherein each ofR^(ya) and R^(yb) is hydrogen.24. The compound according to any of embodiments 1-22, wherein each ofR^(ya) and R^(yb) is deuterium.25. The compound according to embodiment 1, wherein the compound is ofFormulae II, II′, or II″:

or a pharmaceutically acceptable salt thereof.26. The compound according to embodiment 25, wherein the compound isselected from:

Formula Formula Formula II II′ II″ R¹ R^(1′) R^(1″) R² R^(2′) II-1 II′-1II″-1 D H H H H II-2 II′-2 II″-2 H D H H H II-3 II′-3 II″-3 H H D H HII-4 II′-4 II″-4 D D H H H II-5 II′-5 II″-5 D H D H H II-6 II′-6 II″-6 HD D H H II-7 II′-7 II″-7 D D D H H II-8 II′-8 II″-8 H H H H D II-9 II′-9II″-9 D H H H D II-10 II′-10 II″-10 H D H H D II-11 II′-11 II″-11 H H DH D II-12 II′-12 II″-12 D D H H D II-13 II′-13 II″-13 D H D H D II-14II′-14 II″-14 H D D H D II-15 II′-15 II″-15 D D D H D II-16 II′-16II″-16 H H H D H II-17 II′-17 II″-17 D H H D H II-18 II′-18 II″-18 H D HD H II-19 II′-19 II″-19 H H D D H II-20 II′-20 II″-20 D D H D H II-21II′-21 II″-21 D H D D H II-22 II′-22 II″-22 H D D D H II-23 II′-23II″-23 D D D D H II-24 II′-24 II″-24 H H H D D II-25 II′-25 II″-25 D H HD D II-26 II′-26 II″-26 H D H D D II-27 II′-27 II″-27 H H D D D II-28II′-28 II″-28 D D H D D II-29 II′-29 II″-29 D H D D D II-30 II′-30II″-30 H D D D D II-31 II′-31 II″-31 D D D D  D.27. The compound according to embodiment 1, wherein the compound is ofFormulae III, III′, or III″:

or a pharmaceutically acceptable salt thereof.28. The compound according to embodiment 27, wherein the compound isselected from:

Formula Formula Formula III III′ III″ R¹/R^(1′)/R^(1″) R²/R^(2′)R³/R^(3′) R⁴ III-1 III′-1 III″-1 D H H H III-2 III′-2 III″-2 H D H HIII-3 III′-3 III″-3 H H D H III-4 III′-4 III″-4 D D H H III-5 III′-5III″-5 D H D H III-6 III′-6 III″-6 H D D H III-7 III′-7 III″-7 D D D HIII-8 III′-8 III″-8 H H H D III-9 III′-9 III″-9 D H H D III-10 III′-10III″-10 H D H D III-11 III′-11 III″-11 H H D D III-12 III′-12 III″-12 DD H D III-13 III′-13 III″-13 D H D D III-14 III′-14 III″-14 H D D DIII-15 III′-15 III″-15 D D D  D.29. The compound according to embodiment 1, wherein the compound is ofFormulae IV, IV′, or IV″:

or a pharmaceutically acceptable salt thereof.30. The compound according to embodiment 29, wherein the compound isselected from:

Formula Formula Formula IV IV′ IV″ R⁷ R^(7′) R⁸ R^(8′) R^(8″) R⁹ IV-1IV′-1 IV″-1 H H D H H H IV-2 IV′-2 IV″-2 H H H D H H IV-3 IV′-3 IV″-3 HH H H D H IV-4 IV′-4 IV″-4 H H D D H H IV-5 IV′-5 IV″-5 H H D H D H IV-6IV′-6 IV″-6 H H H D D H IV-7 IV′-7 IV″-7 H H D D D H IV-8 IV′-8 IV″-8 HD H H H H IV-9 IV′-9 IV″-9 H D D H H H IV-10 IV′-10 IV′-10 H D H D H HIV-11 IV′-11 IV″-11 H D H H D H IV-12 IV′-12 IV″-12 H D D D H H IV-13IV′-13 IV″-13 H D D H D H IV-14 IV′-14 IV″-14 H D H D D H IV-15 IV′-15IV″-15 H D D D D H IV-16 IV′-16 IV″-16 D H H H H H IV-17 IV′-17 IV″-17 DH D H H H IV-18 IV′-18 IV″-18 D H H D H H IV-19 IV′-19 IV″-19 D H H H DH IV-20 IV′-20 IV″-20 D H D D H H IV-21 IV′-21 IV″-21 D H D H D H IV-22IV′-22 IV″-22 D H H D D H IV-23 IV′-23 IV″-23 D H D D D H IV-24 IV′-24IV″-24 D D H H H H IV-25 IV′-25 IV″-25 D D D H H H IV-26 IV′-26 IV″-26 DD H D H H IV-27 IV′-27 IV″-27 D D H H D H IV-28 IV′-28 IV″-28 D D D D HH IV-29 IV′-29 IV″-29 D D D H D H IV-30 IV′-30 IV″-30 D D H D D H IV-31IV′-31 IV″-31 D D D D D H IV-32 IV′-32 IV″-32 H H H H H D IV-33 IV′-33IV″-33 H H D H H D IV-34 IV′-34 IV″-34 H H H D H D IV-35 IV′-35 IV″-35 HH H H D D IV-36 IV′-36 IV″-36 H H D D H D IV-37 IV′-37 IV″-37 H H D H DD IV-38 IV′-38 IV″-38 H H H D D D IV-39 IV′-39 IV″-39 H H D D D D IV-40IV′-40 IV″-40 H D H H H D IV-41 IV′-41 IV″-41 H D D H H D IV-42 IV′-42IV″-42 H D H D H D IV-43 IV′-43 IV″-43 H D H H D D IV-44 IV′-44 IV″-44 HD D D H D IV-45 IV′-45 IV″-45 H D D H D D IV-46 IV′-46 IV″-46 H D H D DD IV-47 IV′-47 IV″-47 H D D D D D IV-48 IV′-48 IV″-48 D H H H H D IV-49IV′-49 IV″-49 D H D H H D IV-50 IV′-50 IV″-50 D H H D H D IV-51 IV′-51IV″-51 D H H H D D IV-52 IV′-52 IV″-52 D H D D H D IV-53 IV′-53 IV″-53 DH D H D D IV-54 IV′-54 IV″-54 D H H D D D IV-55 IV′-55 IV″-55 D H D D DD IV-56 IV′-56 IV″-56 D D H H H D IV-57 IV′-57 IV″-57 D D D H H D IV-58IV′-58 IV″-58 D D H D H D IV-59 IV′-59 IV″-59 D D H H D D IV-60 IV′-60IV″-60 D D D D H D IV-61 IV′-61 IV″-61 D D D H D D IV-62 IV′-62 IV″-62 DD H D D D IV-63 IV′-63 IV″-63 D D D D D  D.31. The compound according to embodiment 1, wherein the compound is ofFormulae V, V′, or V″.

or a pharmaceutically acceptable salt thereof.32. The compound according to embodiment 31, wherein the compound isselected from:

Formula Formula Formula R¹/R^(1′)/ R⁸/R^(8′)/ V V′ V″ R^(1″) R²/R^(2′)R⁷/R^(7′) R^(8″) R⁹ V-1 V′-1 V″-1 D H D H H V-2 V′-2 V″-2 D H H D H V-3V′-3 V″-3 D H H H D V-4 V′-4 V″-4 D H D D H V-5 V′-5 V″-5 D H D H D V-6V′-6 V″-6 D H H D D V-7 V′-7 V″-7 D H D D D V-8 V′-8 V″-8 H D D H H V-9V′-9 V″-9 H D H D H V-10 V′-10 V″-10 H D H H D V-11 V′-11 V″-11 H D D DH V-12 V′-12 V″-12 H D D H D V-13 V′-13 V″-13 H D H D D V-14 V′-14 V″-14H D D D D V-15 V′-15 V″-15 D D D H H V-16 V′-16 V″-16 D D H D H V-17V′-17 V″-17 D D H H D V-18 V′-18 V″-18 D D D D H V-19 V′-19 V″-19 D D DH D V-20 V′-20 V″-20 D D H D D V-21 V′-21 V″-21 D D D D  D.33. The compound according to embodiment 1, wherein the compound is ofFormulae VI,

or a pharmaceutically acceptable salt thereof.34. The compound according to embodiment 33, wherein each of R^(ya) andR^(yb) is hydrogen and the compound is selected from:

Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/ R⁸/R^(8′)/ VI VI′ VI″ R^(1″)R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb) VI-1 VI′-1 VI″-1 H H H H H H DVI-2 VI′-2 VI″-2 H H D H H H D VI-3 VI′-3 VI″-3 H H H D H H D VI-4 VI′-4VI″-4 H H H H D H D VI-5 VI′-5 VI″-5 H H D D H H D VI-6 VI′-6 VI″-6 H HD H D H D VI-7 VI′-7 VI″-7 H H H D D H D VI-8 VI′-8 VI″-8 H H D D D H DVI-9 VI′-9 VI″-9 H D H H H H D VI-10 VI′-10 VI″-10 H D D H H H D VI-11VI′-11 VI″-11 H D H D H H D VI-12 VI′-12 VI″-12 H D H H D H D VI-13VI′-13 VI″-13 H D D D H H D VI-14 VI′-14 VI″-14 H D D H D H D VI-15VI′-15 VI″-15 H D H D D H D VI-16 VI′-16 VI″-16 H D D D D H D VI-17VI′-17 VI″-17 D H H H H H D VI-18 VI′-18 VI″-18 D H D H H H D VI-19VI′-19 VI″-19 D H H D H H D VI-20 VI′-20 VI″-20 D H H H D H D VI-21VI′-21 VI″-21 D H D D H H D VI-22 VI′-22 VI″-22 D H D H D H D VI-23VI′-23 VI″-23 D H H D D H D VI-24 VI′-24 VI″-24 D H D D D H D VI-25VI′-25 VI″-25 D D H H H H D VI-26 VI′-26 VI″-26 D D D H H H D VI-27VI′-27 VI″-27 D D H D H H D VI-28 VI′-28 VI″-28 D D H H D H D VI-29VI′-29 VI″-29 D D D D H H D VI-30 VI′-30 VI″-30 D D D H D H D VI-31VI′-31 VI″-31 D D H D D H D VI-32 VI′-32 VI″-32 D D D D D H D VI-33VI′-33 VI″-33 H H H H H D H VI-34 VI′-34 VI″-34 H H D H H D H VI-35VI′-35 VI″-35 H H H D H D H VI-36 VI′-36 VI″-36 H H H H D D H VI-37VI′-37 VI″-37 H H D D H D H VI-38 VI′-38 VI″-38 H H D H D D H VI-39VI′-39 VI″-39 H H H D D D H VI-40 VI′-40 VI″-40 H H D D D D H VI-41VI′-41 VI″-41 H D H H H D H VI-42 VI′-42 VI″-42 H D D H H D H VI-43VI′-43 VI″-43 H D H D H D H VI-44 VI′-44 VI″-44 H D H H D D H VI-45VI′-45 VI″-45 H D D D H D H VI-46 VI′-46 VI″-46 H D D H D D H VI-47VI′-47 VI″-47 H D H D D D H VI-48 VI′-48 VI″-48 H D D D D D H VI-49VI′-49 VI″-49 D H H H H D H VI-50 VI′-50 VI″-50 D H D H H D H VI-51VI′-51 VI″-51 D H H D H D H VI-52 VI′-52 VI″-52 D H H H D D H VI-53VI′-53 VI″-53 D H D D H D H VI-54 VI′-54 VI″-54 D H D H D D H VI-55VI′-55 VI″-55 D H H D D D H VI-56 VI′-56 VI″-56 D H D D D D H VI-57VI′-57 VI″-57 D D H H H D H VI-58 VI′-58 VI″-58 D D D H H D H VI-59VI′-59 VI″-59 D D H D H D H VI-60 VI′-60 VI″-60 D D H H D D H VI-61VI′-61 VI″-61 D D D D H D H VI-62 VI′-62 VI″-62 D D D H D D H VI-63VI′-63 VI″-63 D D H D D D H VI-64 VI′-64 VI″-64 D D D D D D H VI-65VI′-65 VI″-65 H H H H H D D VI-66 VI′-66 VI″-66 H H D H H D D VI-67VI′-67 VI″-67 H H H D H D D VI-68 VI′-68 VI″-68 H H H H D D D VI-69VI′-69 VI″-69 H H D D H D D VI-70 VI′-70 VI″-70 H H D H D D D VI-71VI′-71 VI″-71 H H H D D D D VI-72 VI′-72 VI″-72 H H D D D D D VI-73VI′-73 VI″-73 H D H H H D D VI-74 VI′-74 VI″-74 H D D H H D D VI-75VI′-75 VI″-75 H D H D H D D VI-76 VI′-76 VI″-76 H D H H D D D VI-77VI′-77 VI″-77 H D D D H D D VI-78 VI′-78 VI″-78 H D D H D D D VI-79VI′-79 VI″-79 H D H D D D D VI-80 VI′-80 VI″-80 H D D D D D D VI-81VI′-81 VI″-81 D H H H H D D VI-82 VI′-82 VI″-82 D H D H H D D VI-83VI′-83 VI″-83 D H H D H D D VI-84 VI′-84 VI″-84 D H H H D D D VI-85VI′-85 VI″-85 D H D D H D D VI-86 VI′-86 VI″-86 D H D H D D D VI-87VI′-87 VI″-87 D H H D D D D VI-88 VI′-88 VI″-88 D H D D D D D VI-89VI′-89 VI″-89 D D H H H D D VI-90 VI′-90 VI″-90 D D D H H D D VI-91VI′-91 VI″-91 D D H D H D D VI-92 VI′-92 VI″-92 D D H H D D D VI-93VI′-93 VI″-93 D D D D H D D VI-94 VI′-94 VI″-94 D D D H D D D VI-95VI′-95 VI″-95 D D H D D D D VI-96 VI′-96 VI″-96 D D D D D D  D.35. The compound according to embodiment 33, wherein each of R^(ya) andR^(yb) is deuterium and the compound is selected from:

Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/ R⁸/R^(8′)/ VI VI′ VI″ R^(1″)R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb) VI-97 VI′-97 VI″-97 H H H H H H HVI-98 VI′-98 VI″-98 H H D H H H H VI-99 VI′-99 VI″-99 H H H D H H HVI-100 VI′-100 VI″-100 H H H H D H H VI-101 VI′-101 VI″-101 H H D D H HH VI-102 VI′-102 VI″-102 H H D H D H H VI-103 VI′-103 VI″-103 H H H D DH H VI-104 VI′-104 VI″-104 H H D D D H H VI-105 VI′-105 VI″-105 H D H HH H H VI-106 VI′-106 VI″-106 H D D H H H H VI-107 VI′-107 VI″-107 H D HD H H H VI-108 VI′-108 VI″-108 H D H H D H H VI-109 VI′-109 VI″-109 H DD D H H H VI-110 VI′-110 VI″-110 H D D H D H H VI-111 VI′-111 VI″-111 HD H D D H H VI-112 VI′-112 VI″-112 H D D D D H H VI-113 VI′-113 VI″-113D H H H H H H VI-114 VI′-114 VI″-114 D H D H H H H VI-115 VI′-115VI″-115 D H H D H H H VI-116 VI′-116 VI″-116 D H H H D H H VI-117VI′-117 VI″-117 D H D D H H H VI-118 VI′-118 VI″-118 D H D H D H HVI-119 VI′-119 VI″-119 D H H D D H H VI-120 VI′-120 VI″-120 D H D D D HH VI-121 VI′-121 VI″-121 D D H H H H H VI-122 VI′-122 VI″-122 D D D H HH H VI-123 VI′-123 VI″-123 D D H D H H H VI-124 VI′-124 VI″-124 D D H HD H H VI-125 VI′-125 VI″-125 D D D D H H H VI-126 VI′-126 VI″-126 D D DH D H H VI-127 VI′-127 VI″-127 D D H D D H H VI-128 VI′-128 VI″-128 D DD D D H H VI-129 VI′-129 VI″-129 H H H H H H D VI-130 VI′-130 VI″-130 HH D H H H D VI-131 VI′-131 VI″-131 H H H D H H D VI-132 VI′-132 VI″-132H H H H D H D VI-133 VI′-133 VI″-133 H H D D H H D VI-134 VI′-134VI″-134 H H D H D H D VI-135 VI′-135 VI″-135 H H H D D H D VI-136VI′-136 VI″-136 H H D D D H D VI-137 VI′-137 VI″-137 H D H H H H DVI-138 VI′-138 VI″-138 H D D H H H D VI-139 VI′-139 VI″-139 H D H D H HD VI-140 VI′-140 VI″-140 H D H H D H D VI-141 VI′-141 VI″-141 H D D D HH D VI-142 VI′-142 VI″-142 H D D H D H D VI-143 VI′-143 VI″-143 H D H DD H D VI-144 VI′-144 VI″-144 H D D D D H D VI-145 VI′-145 VI″-145 D H HH H H D VI-146 VI′-146 VI″-146 D H D H H H D VI-147 VI′-147 VI″-147 D HH D H H D VI-148 VI′-148 VI″-148 D H H H D H D VI-149 VI′-149 VI″-149 DH D D H H D VI-150 VI′-150 VI″-150 D H D H D H D VI-151 VI′-151 VI″-151D H H D D H D VI-152 VI′-152 VI″-152 D H D D D H D VI-153 VI′-153VI″-153 D D H H H H D VI-154 VI′-154 VI″-154 D D D H H H D VI-155VI′-155 VI″-155 D D H D H H D VI-156 VI′-156 VI″-156 D D H H D H DVI-157 VI′-157 VI″-157 D D D D H H D VI-158 VI′-158 VI″-158 D D D H D HD VI-159 VI′-159 VI″-159 D D H D D H D VI-160 VI′-160 VI″-160 D D D D DH D VI-161 VI′-161 VI″-161 H H H H H D H VI-162 VI′-162 VI″-162 H H D HH D H VI-163 VI′-163 VI″-163 H H H D H D H VI-164 VI′-164 VI″-164 H H HH D D H VI-165 VI′-165 VI″-165 H H D D H D H VI-166 VI′-166 VI″-166 H HD H D D H VI-167 VI′-167 VI″-167 H H H D D D H VI-168 VI′-168 VI″-168 HH D D D D H VI-169 VI′-169 VI″-169 H D H H H D H VI-170 VI′-170 VI″-170H D D H H D H VI-171 VI′-171 VI″-171 H D H D H D H VI-172 VI′-172VI″-172 H D H H D D H VI-173 VI′-173 VI″-173 H D D D H D H VI-174VI′-174 VI″-174 H D D H D D H VI-175 VI′-175 VI″-175 H D H D D D HVI-176 VI′-176 VI″-176 H D D D D D H VI-177 VI′-177 VI″-177 D H H H H DH VI-178 VI′-178 VI″-178 D H D H H D H VI-179 VI′-179 VI″-179 D H H D HD H VI-180 VI′-180 VI″-180 D H H H D D H VI-181 VI′-181 VI″-181 D H D DH D H VI-182 VI′-182 VI″-182 D H D H D D H VI-183 VI′-183 VI″-183 D H HD D D H VI-184 VI′-184 VI″-184 D H D D D D H VI-185 VI′-185 VI″-185 D DH H H D H VI-186 VI′-186 VI″-186 D D D H H D H VI-187 VI′-187 VI″-187 DD H D H D H VI-188 VI′-188 VI″-188 D D H H D D H VI-189 VI′-189 VI″-189D D D D H D H VI-190 VI′-190 VI″-190 D D D H D D H VI-191 VI′-191VI″-191 D D H D D D H VI-192 VI′-192 VI″-192 D D D D D D H VI-193VI′-193 VI″-193 H H H H H D D VI-194 VI′-194 VI″-194 H H D H H D DVI-195 VI′-195 VI″-195 H H H D H D D VI-196 VI′-196 VI″-196 H H H H D DD VI-197 VI′-197 VI″-197 H H D D H D D VI-198 VI′-198 VI″-198 H H D H DD D VI-199 VI′-199 VI″-199 H H H D D D D VI-200 VI′-200 VI″-200 H H D DD D D VI-201 VI′-201 VI″-201 H D H H H D D VI-202 VI′-202 VI″-202 H D DH H D D VI-203 VI′-203 VI″-203 H D H D H D D VI-204 VI′-204 VI″-204 H DH H D D D VI-205 VI′-205 VI″-205 H D D D H D D VI-206 VI′-206 VI″-206 HD D H D D D VI-207 VI′-207 VI″-207 H D H D D D D VI-208 VI′-208 VI″-208H D D D D D D VI-209 VI′-209 VI″-209 D H H H H D D VI-210 VI′-210VI″-210 D H D H H D D VI-211 VI′-211 VI″-211 D H H D H D D VI-212VI′-212 VI″-212 D H H H D D D VI-213 VI′-213 VI″-213 D H D D H D DVI-214 VI′-214 VI″-214 D H D H D D D VI-215 VI′-215 VI″-215 D H H D D DD VI-216 VI′-216 VI″-216 D H D D D D D VI-217 VI′-217 VI″-217 D D H H HD D VI-218 VI′-218 VI″-218 D D D H H D D VI-219 VI′-219 VI″-219 D D H DH D D VI-220 VI′-220 VI″-220 D D H H D D D VI-221 VI′-221 VI″-221 D D DD H D D VI-222 VI′-222 VI″-222 D D D H D D D VI-223 VI′-223 VI″-223 D DH D D D D VI-224 VI′-224 VI″-224 D D D D D D  D.36. The compound according to embodiment 33, wherein each of R^(ya) ishydrogen and R^(yb) is deuterium and the compound is selected from:

Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/ R⁸/R^(8′)/ VI VI′ VI″ R^(1″)R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb) VI-225 VI′-225 VI″-225 H H H H H HH VI-226 VI′-226 VI″-226 H H D H H H H VI-227 VI′-227 VI″-227 H H H D HH H VI-228 VI′-228 VI″-228 H H H H D H H VI-229 VI′-229 VI″-229 H H D DH H H VI-230 VI′-230 VI″-230 H H D H D H H VI-231 VI′-231 VI″-231 H H HD D H H VI-232 VI′-232 VI″-232 H H D D D H H VI-233 VI′-233 VI″-233 H DH H H H H VI-234 VI′-234 VI″-234 H D D H H H H VI-235 VI′-235 VI″-235 HD H D H H H VI-236 VI′-236 VI″-236 H D H H D H H VI-237 VI′-237 VI″-237H D D D H H H VI-238 VI′-238 VI″-238 H D D H D H H VI-239 VI′-239VI″-239 H D H D D H H VI-240 VI′-240 VI″-240 H D D D D H H VI-241VI′-241 VI″-241 D H H H H H H VI-242 VI′-242 VI″-242 D H D H H H HVI-243 VI′-243 VI″-243 D H H D H H H VI-244 VI′-244 VI″-244 D H H H D HH VI-245 VI′-245 VI″-245 D H D D H H H VI-246 VI′-246 VI″-246 D H D H DH H VI-247 VI′-247 VI″-247 D H H D D H H VI-248 VI′-248 VI″-248 D H D DD H H VI-249 VI′-249 VI″-249 D D H H H H H VI-250 VI′-250 VI″-250 D D DH H H H VI-251 VI′-251 VI″-251 D D H D H H H VI-252 VI′-252 VI″-252 D DH H D H H VI-253 VI′-253 VI″-253 D D D D H H H VI-254 VI′-254 VI″-254 DD D H D H H VI-255 VI′-255 VI″-255 D D H D D H H VI-256 VI′-256 VI″-256D D D D D H H VI-257 VI′-257 VI″-257 H H H H H H D VI-258 VI′-258VI″-258 H H D H H H D VI-259 VI′-259 VI″-259 H H H D H H D VI-260VI′-260 VI″-260 H H H H D H D VI-261 VI′-261 VI″-261 H H D D H H DVI-262 VI′-262 VI″-262 H H D H D H D VI-263 VI′-263 VI″-263 H H H D D HD VI-264 VI′-264 VI″-264 H H D D D H D VI-265 VI′-265 VI″-265 H D H H HH D VI-266 VI′-266 VI″-266 H D D H H H D VI-267 VI′-267 VI″-267 H D H DH H D VI-268 VI′-268 VI″-268 H D H H D H D VI-269 VI′-269 VI″-269 H D DD H H D VI-270 VI′-270 VI″-270 H D D H D H D VI-271 VI′-271 VI″-271 H DH D D H D VI-272 VI′-272 VI″-272 H D D D D H D VI-273 VI′-273 VI″-273 DH H H H H D VI-274 VI′-274 VI″-274 D H D H H H D VI-275 VI′-275 VI″-275D H H D H H D VI-276 VI′-276 VI″-276 D H H H D H D VI-277 VI′-277VI″-277 D H D D H H D VI-278 VI′-278 VI″-278 D H D H D H D VI-279VI′-279 VI″-279 D H H D D H D VI-280 VI′-280 VI″-280 D H D D D H DVI-281 VI′-281 VI″-281 D D H H H H D VI-282 VI′-282 VI″-282 D D D H H HD VI-283 VI′-283 VI″-283 D D H D H H D VI-284 VI′-284 VI″-284 D D H H DH D VI-285 VI′-285 VI″-285 D D D D H H D VI-286 VI′-286 VI″-286 D D D HD H D VI-287 VI′-287 VI″-287 D D H D D H D VI-288 VI′-288 VI″-288 D D DD D H D VI-289 VI′-289 VI″-289 H H H H H D H VI-290 VI′-290 VI″-290 H HD H H D H VI-291 VI′-291 VI″-291 H H H D H D H VI-292 VI′-292 VI″-292 HH H H D D H VI-293 VI′-293 VI″-293 H H D D H D H VI-294 VI′-294 VI″-294H H D H D D H VI-295 VI′-295 VI″-295 H H H D D D H VI-296 VI′-296VI″-296 H H D D D D H VI-297 VI′-297 VI″-297 H D H H H D H VI-298VI′-298 VI″-298 H D D H H D H VI-299 VI′-299 VI″-299 H D H D H D HVI-300 VI′-300 VI″-300 H D H H D D H VI-301 VI′-301 VI″-301 H D D D H DH VI-302 VI′-302 VI″-302 H D D H D D H VI-303 VI′-303 VI″-303 H D H D DD H VI-304 VI′-304 VI″-304 H D D D D D H VI-305 VI′-305 VI″-305 D H H HH D H VI-306 VI′-306 VI″-306 D H D H H D H VI-307 VI′-307 VI″-307 D H HD H D H VI-308 VI′-308 VI″-308 D H H H D D H VI-309 VI′-309 VI″-309 D HD D H D H VI-310 VI′-310 VI″-310 D H D H D D H VI-311 VI′-311 VI″-311 DH H D D D H VI-312 VI′-312 VI″-312 D H D D D D H VI-313 VI′-313 VI″-313D D H H H D H VI-314 VI′-314 VI″-314 D D D H H D H VI-315 VI′-315VI″-315 D D H D H D H VI-316 VI′-316 VI″-316 D D H H D D H VI-317VI′-317 VI″-317 D D D D H D H VI-318 VI′-318 VI″-318 D D D H D D HVI-319 VI′-319 VI″-319 D D H D D D H VI-320 VI′-320 VI″-320 D D D D D DH VI-321 VI′-321 VI″-321 H H H H H D D VI-322 VI′-322 VI″-322 H H D H HD D VI-323 VI′-323 VI″-323 H H H D H D D VI-324 VI′-324 VI″-324 H H H HD D D VI-325 VI′-325 VI″-325 H H D D H D D VI-326 VI′-326 VI″-326 H H DH D D D VI-327 VI′-327 VI″-327 H H H D D D D VI-328 VI′-328 VI″-328 H HD D D D D VI-329 VI′-329 VI″-329 H D H H H D D VI-330 VI′-330 VI″-330 HD D H H D D VI-331 VI′-331 VI″-331 H D H D H D D VI-332 VI′-332 VI″-332H D H H D D D VI-333 VI′-333 VI″-333 H D D D H D D VI-334 VI′-334VI″-334 H D D H D D D VI-335 VI′-335 VI″-335 H D H D D D D VI-336VI′-336 VI″-336 H D D D D D D VI-337 VI′-337 VI″-337 D H H H H D DVI-338 VI′-338 VI″-338 D H D H H D D VI-339 VI′-339 VI″-339 D H H D H DD VI-340 VI′-340 VI″-340 D H H H D D D VI-341 VI′-341 VI″-341 D H D D HD D VI-342 VI′-342 VI″-342 D H D H D D D VI-343 VI′-343 VI″-343 D H H DD D D VI-344 VI′-344 VI″-344 D H D D D D D VI-345 VI′-345 VI″-345 D D HH H D D VI-346 VI′-346 VI″-346 D D D H H D D VI-347 VI′-347 VI″-347 D DH D H D D VI-348 VI′-348 VI″-348 D D H H D D D VI-349 VI′-349 VI″-349 DD D D H D D VI-350 VI′-350 VI″-350 D D D H D D D VI-351 VI′-351 VI″-351D D H D D D D VI-352 VI′-352 VI″-352 D D D D D D  D.37. The compound according to embodiment 33, wherein each of R^(ya) isdeuterium and R^(yb) is hydrogen and the compound is selected from:

Formula Formula Formula R¹/R^(1′)/ R²/ R⁷/ R⁸/R^(8′)/ VI VI′ VI″ R^(1″)R^(2′) R^(7′) R^(8″) R⁹ R^(xa) R^(xb) VI-353 VI′-353 VI″-353 H H H H H HH VI-354 VI′-354 VI″-354 H H D H H H H VI-355 VI′-355 VI″-355 H H H D HH H VI-356 VI′-356 VI″-356 H H H H D H H VI-357 VI′-357 VI″-357 H H D DH H H VI-358 VI′-358 VI″-358 H H D H D H H VI-359 VI′-359 VI″-359 H H HD D H H VI-360 VI′-360 VI″-360 H H D D D H H VI-361 VI′-361 VI″-361 H DH H H H H VI-362 VI′-362 VI″-362 H D D H H H H VI-363 VI′-363 VI″-363 HD H D H H H VI-364 VI′-364 VI″-364 H D H H D H H VI-365 VI′-365 VI″-365H D D D H H H VI-366 VI′-366 VI″-366 H D D H D H H VI-367 VI′-367VI″-367 H D H D D H H VI-368 VI′-368 VI″-368 H D D D D H H VI-369VI′-369 VI″-369 D H H H H H H VI-370 VI′-370 VI″-370 D H D H H H HVI-371 VI′-371 VI″-371 D H H D H H H VI-372 VI′-372 VI″-372 D H H H D HH VI-373 VI′-373 VI″-373 D H D D H H H VI-374 VI′-374 VI″-374 D H D H DH H VI-375 VI′-375 VI″-375 D H H D D H H VI-376 VI′-376 VI″-376 D H D DD H H VI-377 VI′-377 VI″-377 D D H H H H H VI-378 VI′-378 VI″-378 D D DH H H H VI-379 VI′-379 VI″-379 D D H D H H H VI-380 VI′-380 VI″-380 D DH H D H H VI-381 VI′-381 VI″-381 D D D D H H H VI-382 VI′-382 VI″-382 DD D H D H H VI-383 VI′-383 VI″-383 D D H D D H H VI-384 VI′-384 VI″-384D D D D D H H VI-385 VI′-385 VI″-385 H H H H H H D VI-386 VI′-386VI″-386 H H D H H H D VI-387 VI′-387 VI″-387 H H H D H H D VI-388VI′-388 VI″-388 H H H H D H D VI-389 VI′-389 VI″-389 H H D D H H DVI-390 VI′-390 VI″-390 H H D H D H D VI-391 VI′-391 VI″-391 H H H D D HD VI-392 VI′-392 VI″-392 H H D D D H D VI-393 VI′-393 VI″-393 H D H H HH D VI-394 VI′-394 VI″-394 H D D H H H D VI-395 VI′-395 VI″-395 H D H DH H D VI-396 VI′-396 VI″-396 H D H H D H D VI-397 VI′-397 VI″-397 H D DD H H D VI-398 VI′-398 VI″-398 H D D H D H D VI-399 VI′-399 VI″-399 H DH D D H D VI-400 VI′-400 VI″-400 H D D D D H D VI-401 VI′-401 VI″-401 DH H H H H D VI-402 VI′-402 VI″-402 D H D H H H D VI-403 VI′-403 VI″-403D H H D H H D VI-404 VI′-404 VI″-404 D H H H D H D VI-405 VI′-405VI″-405 D H D D H H D VI-406 VI′-406 VI″-406 D H D H D H D VI-407VI′-407 VI″-407 D H H D D H D VI-408 VI′-408 VI″-408 D H D D D H DVI-409 VI′-409 VI″-409 D D H H H H D VI-410 VI′-410 VI″-410 D D D H H HD VI-411 VI′-411 VI″-411 D D H D H H D VI-412 VI′-412 VI″-412 D D H H DH D VI-413 VI′-413 VI″-413 D D D D H H D VI-414 VI′-414 VI″-414 D D D HD H D VI-415 VI′-415 VI″-415 D D H D D H D VI-416 VI′-416 VI″-416 D D DD D H D VI-417 VI′-417 VI″-417 H H H H H D H VI-418 VI′-418 VI″-418 H HD H H D H VI-419 VI′-419 VI″-419 H H H D H D H VI-420 VI′-420 VI″-420 HH H H D D H VI-421 VI′-421 VI″-421 H H D D H D H VI-422 VI′-422 VI″-422H H D H D D H VI-423 VI′-423 VI″-423 H H H D D D H VI-424 VI′-424VI″-424 H H D D D D H VI-425 VI′-425 VI″-425 H D H H H D H VI-426VI′-426 VI″-426 H D D H H D H VI-427 VI′-427 VI″-427 H D H D H D HVI-428 VI′-428 VI″-428 H D H H D D H VI-429 VI′-429 VI″-429 H D D D H DH VI-430 VI′-430 VI″-430 H D D H D D H VI-431 VI′-431 VI″-431 H D H D DD H VI-432 VI′-432 VI″-432 H D D D D D H VI-433 VI′-433 VI″-433 D H H HH D H VI-434 VI′-434 VI″-434 D H D H H D H VI-435 VI′-435 VI″-435 D H HD H D H VI-436 VI′-436 VI″-436 D H H H D D H VI-437 VI′-437 VI″-437 D HD D H D H VI-438 VI′-438 VI″-438 D H D H D D H VI-439 VI′-439 VI″-439 DH H D D D H VI-440 VI′-440 VI″-440 D H D D D D H VI-441 VI′-441 VI″-441D D H H H D H VI-442 VI′-442 VI″-442 D D D H H D H VI-443 VI′-443VI″-443 D D H D H D H VI-444 VI′-444 VI″-444 D D H H D D H VI-445VI′-445 VI″-445 D D D D H D H VI-446 VI′-446 VI″-446 D D D H D D HVI-447 VI′-447 VI″-447 D D H D D D H VI-448 VI′-448 VI″-448 D D D D D DH VI-449 VI′-449 VI″-449 H H H H H D D VI-450 VI′-450 VI″-450 H H D H HD D VI-451 VI′-451 VI″-451 H H H D H D D VI-452 VI′-452 VI″-452 H H H HD D D VI-453 VI′-453 VI″-453 H H D D H D D VI-454 VI′-454 VI″-454 H H DH D D D VI-455 VI′-455 VI″-455 H H H D D D D VI-456 VI′-456 VI″-456 H HD D D D D VI-457 VI′-457 VI″-457 H D H H H D D VI-458 VI′-458 VI″-458 HD D H H D D VI-459 VI′-459 VI″-459 H D H D H D D VI-460 VI′-460 VI″-460H D H H D D D VI-461 VI′-461 VI″-461 H D D D H D D VI-462 VI′-462VI″-462 H D D H D D D VI-463 VI′-463 VI″-463 H D H D D D D VI-464VI′-464 VI″-464 H D D D D D D VI-465 VI′-465 VI″-465 D H H H H D DVI-466 VI′-466 VI″-466 D H D H H D D VI-467 VI′-467 VI″-467 D H H D H DD VI-468 VI′-468 VI″-468 D H H H D D D VI-469 VI′-469 VI″-469 D H D D HD D VI-470 VI′-470 VI″-470 D H D H D D D VI-471 VI′-471 VI″-471 D H H DD D D VI-472 VI′-472 VI″-472 D H D D D D D VI-473 VI′-473 VI″-473 D D HH H D D VI-474 VI′-474 VI″-474 D D D H H D D VI-475 VI′-475 VI″-475 D DH D H D D VI-476 VI′-476 VI″-476 D D H H D D D VI-477 VI′-477 VI″-477 DD D D H D D VI-478 VI′-478 VI″-478 D D D H D D D VI-479 VI′-479 VI″-479D D H D D D D VI-480 VI′-480 VI″-480 D D D D D D  D.38. The compound according to embodiment 1, wherein the compound is ofFormulae VII, VII′, or VII″:

or a pharmaceutically acceptable salt thereof.39. The compound according to embodiment 38, wherein each of R³, R^(3′),and R⁴ are deuterium and the compound is selected from:

Formula Formula Formula R¹/R^(1′)/ R⁸/R^(8′)/ VII VII′ VII″ R^(1″)R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹ VII-1 VII′-1 VII″-1 H H H H H VII-2 VII′-2VII″-2 H H D H H VII-3 VII′-3 VII″-3 H H H D H VII-4 VII′-4 VII″-4 H H HH D VII-5 VII′-5 VII″-5 H H D D H VII-6 VII′-6 VII″-6 H H D H D VII-7VII′-7 VII″-7 H H H D D VII-8 VII′-8 VII″-8 H H D D D VII-9 VII′-9VII″-9 H D H H H VII-10 VII′-10 VII″-10 H D D H H VII-11 VII′-11 VII″-11H D H D H VII-12 VII′-12 VII″-12 H D H H D VII-13 VII′-13 VII″-13 H D DD H VII-14 VII′-14 VII″-14 H D D H D VII-15 VII′-15 VII″-15 H D H D DVII-16 VII′-16 VII″-16 H D D D D VII-17 VII′-17 VII″-17 D H H H H VII-18VII′-18 VII″-18 D H D H H VII-19 VII′-19 VII″-19 D H H D H VII-20VII′-20 VII″-20 D H H H D VII-21 VII′-21 VII″-21 D H D D H VII-22VII′-22 VII″-22 D H D H D VII-23 VII′-23 VII″-23 D H H D D VII-24VII′-24 VII″-24 D H D D D VII-25 VII′-25 VII″-25 D D H H H VII-26VII′-26 VII″-26 D D D H H VII-27 VII′-27 VII″-27 D D H D H VII-28VII′-28 VII″-28 D D H H D VII-29 VII′-29 VII″-29 D D D D H VII-30VII′-30 VII″-30 D D D H D VII-31 VII′-31 VII″-31 D D H D D VII-32VII′-32 VII″-32 D D D D  D.40. The compound according to embodiment 38, wherein each of R³ andR^(3′) is deuterium and R⁴ is hydrogen, and the compound is selectedfrom:

Formula Formula Formula R¹/R^(1′)/ R⁸/R^(8′)/ VII VII′ VII″ R^(1″)R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹ VII-33 VII′-33 VII″-33 H H H H H VII-34VII′-34 VII″-34 H H D H H VII-35 VII′-35 VII″-35 H H H D H VII-36VII′-36 VII″-36 H H H H D VII-37 VII′-37 VII″-37 H H D D H VII-38VII′-38 VII″-38 H H D H D VII-39 VII′-39 VII″-39 H H H D D VII-40VII′-40 VII″-40 H H D D D VII-41 VII′-41 VII″-41 H D H H H VII-42VII′-42 VII″-42 H D D H H VII-43 VII′-43 VII″-43 H D H D H VII-44VII′-44 VII″-44 H D H H D VII-45 VII′-45 VII″-45 H D D D H VII-46VII′-46 VII″-46 H D D H D VII-47 VII′-47 VII″-47 H D H D D VII-48VII′-48 VII″-48 H D D D D VII-49 VII′-49 VII″-49 D H H H H VII-50VII′-50 VII″-50 D H D H H VII-51 VII′-51 VII″-51 D H H D H VII-52VII′-52 VII″-52 D H H H D VII-53 VII′-53 VII″-53 D H D D H VII-54VII′-54 VII″-54 D H D H D VII-55 VII′-55 VII″-55 D H H D D VII-56VII′-56 VII″-56 D H D D D VII-57 VII′-57 VII″-57 D D H H H VII-58VII′-58 VII″-58 D D D H H VII-59 VII′-59 VII″-59 D D H D H VII-60VII′-60 VII″-60 D D H H D VII-61 VII′-61 VII″-61 D D D D H VII-62VII′-62 VII″-62 D D D H D VII-63 VII′-63 VII″-63 D D H D D VII-64VII′-64 VII″-64 D D D D  D.41. The compound according to embodiment 38, wherein each of R³ andR^(3′) is hydrogen and R⁴ is deuterium, and the compound is selectedfrom:

Formula Formula Formula R¹/R^(1′)/ R⁸/R^(8′)/ VII VII′ VII″ R^(1″)R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹ VII-65 VII′-65 VII″-65 H H H H H VII-66VII′-66 VII″-66 H H D H H VII-67 VII′-67 VII″-67 H H H D H VII-68VII′-68 VII″-68 H H H H D VII-69 VII′-69 VII″-69 H H D D H VII-70VII′-70 VII″-70 H H D H D VII-71 VII′-71 VII″-71 H H H D D VII-72VII′-72 VII″-72 H H D D D VII-73 VII′-73 VII″-73 H D H H H VII-74VII′-74 VII″-74 H D D H H VII-75 VII′-75 VII″-75 H D H D H VII-76VII′-76 VII″-76 H D H H D VII-77 VII′-77 VII″-77 H D D D H VII-78VII′-78 VII″-78 H D D H D VII-79 VII′-79 VII″-79 H D H D D VII-80VII′-80 VII″-80 H D D D D VII-81 VII′-81 VII″-81 D H H H H VII-82VII′-82 VII″-82 D H D H H VII-83 VII′-83 VII″-83 D H H D H VII-84VII′-84 VII″-84 D H H H D VII-85 VII′-85 VII″-85 D H D D H VII-86VII′-86 VII″-86 D H D H D VII-87 VII′-87 VII″-87 D H H D D VII-88VII′-88 VII″-88 D H D D D VII-89 VII′-89 VII″-89 D D H H H VII-90VII′-90 VII″-90 D D D H H VII-91 VII′-91 VII″-91 D D H D H VII-92VII′-92 VII″-92 D D H H D VII-93 VII′-93 VII″-93 D D D D H VII-94VII′-94 VII″-94 D D D H D VII-95 VII′-95 VII″-95 D D H D D VII-96VII′-96 VII″-96 D D D D  D.42. The compound according to embodiment 1, wherein the compound is ofFormulae VIII, VIII′, or VIII″:

or a pharmaceutically acceptable salt thereof 43. The compound accordingto embodiment 42, wherein the compound is selected from:

Formula Formula Formula R¹/R^(1′)/ R⁸/R^(8′)/ VIII VIII′ VIII″ R^(1″)R²/R^(2′) R⁷/R^(7′) R^(8″) R⁹ VIII-1 VIII′-1 VIII″-1 H H H H H VIII-2VIII′-2 VIII″-2 H H D H H VIII-3 VIII′-3 VIII″-3 H H H D H VIII-4VIII′-4 VIII″-4 H H H H D VIII-5 VIII′-5 VIII″-5 H H D D H VIII-6VIII′-6 VIII″-6 H H D H D VIII-7 VIII′-7 VIII″-7 H H H D D VIII-8VIII′-8 VIII″-8 H H D D D VIII-9 VIII′-9 VIII″-9 H D H H H VIII-10VIII′-10 VIII″-10 H D D H H VIII-11 VIII′-11 VIII″-11 H D H D H VIII-12VIII′-12 VIII″-12 H D H H D VIII-13 VIII′-13 VIII″-13 H D D D H VIII-14VIII′-14 VIII″-14 H D D H D VIII-15 VIII′-15 VIII″-15 H D H D D VIII-16VIII′-16 VIII″-16 H D D D D VIII-17 VIII′-17 VIII″-17 D H H H H VIII-18VIII′-18 VIII″-18 D H D H H VIII-19 VIII′-19 VIII″-19 D H H D H VIII-20VIII′-20 VIII″-20 D H H H D VIII-21 VIII′-21 VIII″-21 D H D D H VIII-22VIII′-22 VIII″-22 D H D H D VIII-23 VIII′-23 VIII″-23 D H H D D VIII-24VIII′-24 VIII″-24 D H D D D VIII-25 VIII′-25 VIII″-25 D D H H H VIII-26VIII′-26 VIII″-26 D D D H H VIII-27 VIII′-27 VIII″-27 D D H D H VIII-28VIII′-28 VIII″-28 D D H H D VIII-29 VIII′-29 VIII″-29 D D D D H VIII-30VIII′-30 VIII″-30 D D D H D VIII-31 VIII′-31 VIII″-31 D D H D D VIII-32VIII′-32 VIII″-32 D D D D  D.44. The compound according to any of embodiments 1-43, wherein thecompound is other than:

45. A pharmaceutically acceptable composition comprising the compoundaccording to any one of embodiments 1-44 and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.46. A method for inhibiting MK2 kinase, or a mutant thereof, activity ina biological sample comprising the step of contacting said biologicalsample with a compound according to any one of embodiments 1-44.47. A method for inhibiting MK2 kinase, or a mutant thereof, activity ina patient comprising the step of administering to said patient thecomposition according to embodiment 45.48. The method according to embodiment 47, wherein the MK2 kinase, or amutant thereof, activity is inhibited irreversibly.49. The method according to embodiment 48, wherein the MK2 kinase, or amutant thereof, activity is inhibited irreversibly by covalentlymodifying Cys140 of MK2.50. A method for treating an MK2-mediated disease or disorder in apatient in need thereof, comprising the step of administering to saidpatient the composition according to embodiment 45.51. The method according to embodiment 50, wherein the MK2-mediateddisease or disorder is an autoimmune disorder, chronic or acuteinflammatory disorder, an auto-inflammatory disorder, a fibroticdisorder, a metabolic disorder, a neoplasia, or a cardiovascular orcerebrovascular disorder.52. The method according to embodiment 51, wherein the MK2-mediateddisease or disorder is an autoimmune disorder, chronic or acuteinflammatory disorder, or an auto-inflammatory disorder.53. The method according to embodiment 52, wherein the autoimmunedisorder, chronic or acute inflammatory disorder, and/orauto-inflammatory disorder is selected from the group consisting ofinflammatory bowel diseases, ulcerative colitis, Crohn's disease,multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis,osteoarthritis, juvenile arthritis, psoriatic arthritis, reactivearthritis, ankylosing spondylitis, cryopyrin associated periodicsyndromes, Muckle-Wells syndrome, familial cold auto-inflammatorysyndrome, neonatal-onset multisystem inflammatory disease, TNF receptorassociated periodic synderome, acute and chronic pancreatitis,atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders,hepatic fibrosis, idiopathic pulmonary fibrosis, nephropathy,sarcoidosis, scleroderma, anaphylaxis, diabetes, diabetes mellitus type1, diabetes mellitus type 2, diabetic retinopathy, Still's disease,vasculitis, sarcoidosis, pulmonary inflammation, acute respiratorydistress syndrome, wet and dry age-related macular degeneration,autoimmune hemolytic syndromes, autoimmune and inflammatory hepatitis,autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis,autoimmune thrombocytopenia, silicone implant associated autoimmunedisease, Sjogren's syndrome, familial Mediterranean fever, systemiclupus erythematosus, vasculitis syndromes, temporal, Takayasu's andgiant cell arteritis, Behget's disease, Wegener's granulomatosis,vitiligo, secondary hematologic manifestation of autoimmune diseases,anemias, drug-induced autoimmunity, Hashimoto's thyroiditis,hypophysitis, idiopathic thrombocytic pupura, metal-inducedautoimmunity, myasthenia gravis, pemphigus, autoimmune deafness,Meniere's disease, Goodpasture's syndrome, Graves' disease, HW-relatedautoimmune syndromes, Gullain-Barre disease, Addison's disease,anti-phospholipid syndrome, asthma, atopic dermatitis, Celiac disease,Cushing's syndrome, dermatomyositis, idiopathic adrenal adrenal atrophy,idiopathic thrombocytopenia, Kawasaki syndrome, Lambert-Eaton Syndrome,pernicious anemia, pollinosis, polyarteritis nodosa, primary biliarycirrhosis, primary sclerosing cholangitis, Raynaud's, Reiter's Syndrome,relapsing polychondritis, Schmidt's syndrome, thyrotoxidosis, sepsis,septic shock, endotoxic shock, exotoxin-induced toxic shock, gramnegative sepsis, toxic shock syndrome, glomerulonephritis, peritonitis,interstitial cystitis, hyperoxia-induced inflammations, chronicobstructive pulmonary disease (COPD), vasculitis, graft vs. hostreaction, graft vs. host disease, allograft rejections, acute allograftrejection, chronic allograft rejection, early transplantation rejection,acute allograft rejection, reperfusion injury, pain, acute pain, chronicpain, neuropathic pain, fibromyalgia, chronic infections, meningitis,encephalitis, myocarditis, gingivitis, post surgical trauma, tissueinjury, traumatic brain injury, enterocolitis, sinusitis, uveitis,ocular inflammation, optic neuritis, gastric ulcers, esophagitis,peritonitis, periodontitis, dermatomyositis, gastritis, myositis,polymyalgia, pneumonia and bronchitis.54. The method according to embodiment 47, wherein the MK2-mediateddisease or disorder is a fibrotic disorder.55. The method according to embodiment 50, wherein the fibrotic disorderis selected from the group consisting of systemic sclerosis/scleroderma,lupus nephritis, connective tissue disease, wound healing, surgicalscarring, spinal cord injury, CNS scarring, acute lung injury, pulmonaryfibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronicobstructive pulmonary disease, adult respiratory distress syndrome,acute lung injury, drug-induced lung injury, glomerulonephritis, chronickidney disease, diabetic nephropathy, hypertension-induced nephropathy,alimentary track or gastrointestinal fibrosis, renal fibrosis, hepaticor biliary fibrosis, liver fibrosis, nonalcoholic steatohepatitis,hepatitis C, hepatocellular carcinoma, cirrhosis, primary biliarycirrhosis, cirrhosis due to fatty liver disease cirrhosis due toalcoholic fatty liver disease, cirrhosis due to nonalcoholicsteatosis/non-alcoholic fatty liver disease, radiation-induced fibrosishead and neck fibrosis, gastrointestinal fibrosis, pulmonary fibrosis,primary sclerosing cholangitis, restenosis, cardiac fibrosis,endomyocardial fibrosis, atrial fibrosis, opthalmic scarring,fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas,fibrosarcomas, transplant arteriopathy, keloid, mediastinal fibrosis,myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis,and nephrogenic systemic fibrosis.56. The method according to embodiment 51, wherein the MK2-mediateddisease or disorder is a metabolic disorder.57. The method according to embodiment 56, wherein the metabolicdisorder is selected from the group consisting of obesity,steroid-resistance, glucose intolerance, and metabolic syndrome.58. The method according to embodiment 51, wherein the MK2-mediateddisease or disorder is a neoplasia.59. The method according to embodiment 58, wherein the neoplasia isselected from the group consisting of angiogenesis disorders, multiplemyeloma, leukemias, acute lymphocytic leukemia, acute and chronicmyelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, promyelocytic leukemia, lymphomas, B-cell lymphoma, T-celllymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma,mast cell tumors, Hodgkin's disease, non-Hodgkin's disease,myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma,neuroblastoma, glioma, schwannomas, melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderma pigmentosum, keratoctanthoma, thyroid follicularcancer, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma,metastatic and bone disorders, cancer of the bone, mouth/pharynx,esophagus, larynx, stomach, intestine, colon, rectum, lung, liver,pancreas, nerve, brain, head and neck, throat, ovary, uterus, prostate,testis, bladder, kidney, breast, gall bladder, cervix, thyroid,prostate, and skin, non-small cell lung cancer, small cell lung cancer,glioma, and glioblastoma multiforme.60. The method according to embodiment 46 wherein the MK2-mediateddisease or disorder is a cardiovascular or cerebrovascular disorder.61. The method according to embodiment 60, wherein the cardiovascular orcerebrovascular disorder is selected from the group consisting ofatherosclerosis, restenosis of an atherosclerotic coronary artery, acutecoronary syndrome, myocardial infarction, cardiac-allograftvasculopathy, stroke, central nervous system disorders with aninflammatory or apoptotic component, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, spinalcord injury, neuronal ischemia and peripheral neuropathy.

We claim:
 1. A compound of Formulae IV, IV′, or IV″:

or a pharmaceutically acceptable salt thereof, whererin: each of R⁷,R^(7′), R⁸, R^(8′), R^(8″), and R⁹ is independently selected fromhydrogen or deuterium; provided that at least one of R⁷, R^(7′), R⁸,R^(8′), R^(8″), and R⁹ is deuterium.
 2. The compound according to claim1, wherein the compound is selected from: Formula Formula Formula IV IV′IV″ R⁷ R^(7′) R⁸ R^(8′) R^(8″) R⁹ IV-1 IV′-1 IV″-1 H H D H H H IV-2IV′-2 IV″-2 H H H D H H IV-3 IV′-3 IV″-3 H H H H D H IV-4 IV′-4 IV″-4 HH D D H H IV-5 IV′-5 IV″-5 H H D H D H IV-6 IV′-6 IV″-6 H H H D D H IV-7IV′-7 IV″-7 H H D D D H IV-8 IV′-8 IV″-8 H D H H H H IV-9 IV′-9 IV″-9 HD D H H H IV-10 IV′-10 IV″-10 H D H D H H IV-11 IV′-11 IV″-11 H D H H DH IV-12 IV′-12 IV″-12 H D D D H H IV-13 IV′-13 IV″-13 H D D H D H IV-14IV′-14 IV″-14 H D H D D H IV-15 IV′-15 IV″-15 H D D D D H IV-16 IV′-16IV″-16 D H H H H H IV-17 IV′-17 IV″-17 D H D H H H IV-18 IV′-18 IV″-18 DH H D H H IV-19 IV′-19 IV″-19 D H H H D H IV-20 IV′-20 IV″-20 D H D D HH IV-21 IV′-21 IV″-21 D H D H D H IV-22 IV′-22 IV″-22 D H H D D H IV-23IV′-23 IV″-23 D H D D D H IV-24 IV′-24 IV″-24 D D H H H H IV-25 IV′-25IV″-25 D D D H H H IV-26 IV′-26 IV″-26 D D H D H H IV-27 IV′-27 IV″-27 DD H H D H IV-28 IV′-28 IV″-28 D D D D H H IV-29 IV′-29 IV″-29 D D D H DH IV-30 IV′-30 IV″-30 D D H D D H IV-31 IV′-31 IV″-31 D D D D D H IV-32IV′-32 IV″-32 H H H H H D IV-33 IV′-33 IV″-33 H H D H H D IV-34 IV′-34IV″-34 H H H D H D IV-35 IV′-35 IV″-35 H H H H D D IV-36 IV′-36 IV″-36 HH D D H D IV-37 IV′-37 IV″-37 H H D H D D IV-38 IV′-38 IV″-38 H H H D DD IV-39 IV′-39 IV″-39 H H D D D D IV-40 IV′-40 IV″-40 H D H H H D IV-41IV′-41 IV″-41 H D D H H D IV-42 IV′-42 IV″-42 H D H D H D IV-43 IV′-43IV″-43 H D H H D D IV-44 IV′-44 IV″-44 H D D D H D IV-45 IV′-45 IV″-45 HD D H D D IV-46 IV′-46 IV″-46 H D H D D D IV-47 IV′-47 IV″-47 H D D D DD IV-48 IV′-48 IV″-48 D H H H H D IV-49 IV′-49 IV″-49 D H D H H D IV-50IV′-50 IV″-50 D H H D H D IV-51 IV′-51 IV″-51 D H H H D D IV-52 IV′-52IV″-52 D H D D H D IV-53 IV′-53 IV″-53 D H D H D D IV-54 IV′-54 IV″-54 DH H D D D IV-55 IV′-55 IV″-55 D H D D D D IV-56 IV′-56 IV″-56 D D H H HD IV-57 IV′-57 IV″-57 D D D H H D IV-58 IV′-58 IV″-58 D D H D H D IV-59IV′-59 IV″-59 D D H H D D IV-60 IV′-60 IV″-60 D D D D H D IV-61 IV′-61IV″-61 D D D H D D IV-62 IV′-62 IV″-62 D D H D D D IV-63 IV′-63 IV″-63 DD D D D  D.


3. A pharmaceutically acceptable composition comprising the compoundaccording to any one of claims 1 and a pharmaceutically acceptablecarrier, adjuvant, or vehicle.
 4. A method for inhibiting MK2 kinase, ora mutant thereof, activity in a biological sample comprising the step ofcontacting said biological sample with a compound according to any oneof claims
 1. 5. A method for treating an MK2-mediated disease ordisorder in a patient in need thereof, comprising the step ofadministering to said patient the composition according to claim
 3. 6.The compound according to claim 1, wherein each of R⁷ and R^(7″) isdeuterium.
 7. The compound according to claim 1, wherein each of R⁸,R^(8′), and R^(8″) is deuterium.
 8. The compound according to claim 6,wherein each of R⁸, R^(8′), and R^(8″) is deuterium.
 9. The compoundaccording to claim 7, wherein R⁹ is deuterium.
 10. The compoundaccording to claim 6, wherein R⁹ is deuterium.
 11. The compoundaccording to claim 7, wherein R⁹ is deuterium.
 12. The compoundaccording to claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticallyacceptable composition comprising the compound according to claim 12 anda pharmaceutically acceptable carrier, adjuvant, or vehicle.